National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Cardiovasculas

Toxicity of

Cocaine:

Underlying

Mechanisms

1 

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

0 8
Cardiovascular Toxicity

of Cocaine: Underlying

Mechanisms

Editor:

Pushpa Thadani, Ph.D.

Division of Preclinical Research

National Institute on Drug Abuse

Research Monograph 108

1991

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857

For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402
ACKNOWLEDGMENT

This monograph is based on the papers and discussion from a technical

review on “Cardiovascular Toxicity of Cocaine: Underlying Mechanisms,” held

on August 9-10, 1989, in Bethesda, MD. The review meeting was sponsored

by the National institute on Drug Abuse,

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the text. Further reproduction of this copyrighted material is permitted only as

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may be used or reproduced without permission from the Institute or the authors.

Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on Drug

Abuse or any other part of the U.S. Department of Health and Human Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in this

publication are used only because they are considered essential in the context

of the studies reported herein.

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index, Biosciences

Information Service, Chemical Abstracts, Current Contents, Psychological

Abstracts, and Psychopharmacology Abstracts.

DHHS publication number (ADM)91-1767

Printed 1991

i i
Contents

Page

Preface vii

Overview 1

Pushpa V. Thadani

Maternal-Fetal Cardiovascular System: A Target of Cocaine 7

James R. Woods, Jr., and Mark A. Plessinger

Pharmacokinetics and Time-Action Profile of Cocaine in Dogs 28

R. Douglas Wilkerson, Peter N. Temesy-Armos,

and Theodore D. Fraker, Jr.

Acute Tolerance to the Chronotropic Effect of Cocaine in Humans 41

John J. Ambre, Timothy J. Connelly, Tsuen-lh Ruo,

and Thomas K. Henthorn

Mechanisms of Cardiac and Vascular Responses to Cocaine 55

Mark M. Knuepfer, Carrie A. Branch, and

Vernon W. Fischer

Cardiovascular Effects of Cocaine in Squirrel Monkeys 74

Srihari R. Tella, Charles W. Schindler,

and Steven R. Goldberg

iii
Role of the Sympathetic Nervous System in the

Cardiovascular Effects of Cocaine 92

Richard A. Gillis, Lisa C. Bachenheimer,

Kenneth L. Dretchen, Hashim K. Erzouki,

Yvonne M. Hernandez, Rakesh K. Jain,

Muskesh K. Jain, Fred E. Kuhn,

Jack Quest, and Gary L. Schaer

Cocaine-Induced Myocardial Depression 110

Theodore D. Fraker, Jr., Peter N. Temesy-Armos,

and R. Douglas Wilkerson

Prevalence of Myocardial lschemia in Cocaine Addicts 116

Koonlawee Nademanee

Cocaine-Induced Myocardial Infarction:

Clinical Observations and Pathogenetic Considerations 121

Jeffrey M. lsner and Saurabh K. Chokshi

Cardiac Electrophysiological Effects of Cocaine

in Animal Models 131

Peter N. Temesy-Armos, Theodore D. Fraker, Jr.,

and R. Douglas Wilkerson

Effects of Cocaine on Intracellular Calcium Handling

in Cardiac and Vascular Smooth Muscle 139

Cynthia L. Perreault, Kathleen G. Morgan, and

James P. Morgan

Cocaine-Induced Changes in the Biochemistry

and Morphology of Rabbit Aorta 154

Ronald O. Langner and Collette L. Bement

Effects of Cocaine on the Physiology of

Exercise 167

Robert K. Conlee, David W. Barnett, K. Patrick Kelly,

and Dong Ho Han

iv
Effect of Acute Cocaine Administration on

Cardiac and Respiratory Patterning in the

Freely Moving Cat 181

Ronald M. Harper, Rebecca K. Harper,

Robert R. Terreberry, Christopher A. Richard,

and Robert B. Trelease

Direct and Indirect Morphological Markers of

Cocaine Toxicity in the Human Heart 202

Margaret E. Billinghem

Cocaine-Associated Cardiovascular Disease:

Clinical and Pathological Aspects 220

Renu Virmani

List of NIDA Research Monographs 230

v

Preface

On August 9-10, 1989, the National Institute on Drug Abuse held a technical

review meeting titled “Cardiovascular Toxicity of Cocaine: Underlying

Mechanisms” to review the state of knowledge and to identify areas of future

research. Biomedical scientists discussed the potential site(s) of cocaine’s

cardiovascular actions and the possible mechanisms underlying these cardiac

events in immature and mature cardiovascular systems in various animal

models and in human tissues. A report summarizing the major findings and the

future areas of research identified at the meeting was published (Thadani et al.

1990), and included the following summary findings: (1) More than one

mechanism is involved with the deleterious effects of cocaine on myocardium;

(2) pharmacokinetic investigations indicate that in animals and in humans the

elimination of cocaine occurs in a nonlinear fashion, which could cause an

unexpected rise in blood cocaine levels in cocaine addicts during a binge

period; and (3) a subgroup of the population may be more vulnerable to the

cardiotoxic effects of cocaine. Areas of research identified in this field included

more investigations at the cellular and subcellular levels, on the central nervous

system and respiratory system contributions In these cardiac responses, and on

the genetic aspect of cocaine myocardial effects. This monograph consists of

the papers presented at the technical review.

REFERENCE

Thadani, P.V., et al. Cardiovascular toxicity of cocaine: Underlying

mechanisms. J Appl Cardiol 5:317-320, 1990.

vii

Overview

Pushpa V. Thadanl

Use of cocaine during pregnancy has been associated with increased incidence

of miscarriage, rupture of maternal Intracranial aneurysm, abruptio placentae,

and delivery of small-for-gestational-age babies. These pregnancy-related

complications are thought to result from increasing circulating blood

catecholamine levels and vasoconstriction of the regional vascular beds due to

cocaine-induced inhibition of catecholamine reuptake at adrenergic nerve

terminals.

Dr. James Woods, Jr., and Mark Plessinger describe the impact of these

changes on fetal and maternal cardiovascular systems following administration

of cocaine to pregnant ewes. Maternal administration of cocaine produced

dose-dependent increases in maternal heart rate (HR) and blood pressure (BP).

In the fetus, elevations in HR and BP were accompanied by reductions in

arterial PO,. Direct administration of cocaine to the fetus caused no change in

fetal arterial PO, but produced an increase in BP and HR. These findings

indicated that cocaine-induced changes in the fetal cardiovascular system are

the result of the drug’s direct and Indirect effects. Direct effects are caused via

maternal-fetal transfer, whereas indirect actions result from fetal hypoxemia

induced by vasoconstrlction of uterine vasculature. Pharmacological studies

showed that cocaine-evoked vasoconstriction of uterine vasculature involved

stimulation of alpha-adrenergic receptors as well as some other mechanism.

Analysis of cocaine levels in maternal and fetal blood indicated that cocaine

crosses the placenta rapidly and disappears into two vascular compartments

without equilibration.

Because severe cardiopulmonary and neurologic complications also were seen

in pregnant ewes following high doses of cocaine, Dr. Woods and Plessinger

examined the role of pregnancy-related hormones in cocaine-induced

cardiovascular responses. Administration of progesterone to nonpregnant ewes

resulted in cocaine-induced cardiovascular responses similar to those seen in

pregnant animals, suggesting that this hormone may contribute to the amplified

cocaine responses.

1
Recent reports suggest that cocaine-related, life-threatening cardiac events

may not be dependent on the amount of cocaine used. One of the

pharmacological actions of cocaine is to cause vasoconstriction and a decrease

in blood flow, which could limit the drug’s absorption and bioavaiiability-factors

that can vary greatly from one individual to another. To assess the variability of

these factors, Drs. R. Douglas Wilkerson and John Ambre and their respective

colleagues examined, respectively, the pharmacokinetics and time profile of

cocaine in animals and in humans.

Dr. Wiikerson and coworkers showed that cocaine elimination in dogs occurred

in a linear fashion when the dose was below 2 mg/kg and the peak plasma

concentration was below 2 mg/mL. However, at doses above 2 mg/kg, which

produced peak plasma concentration greater than 2 mg/mL, elimination

reverted to zero order.

Dr. Ambre and colleagues describe a nonlinear elimination kinetics for cocaine

in humans over a range of doses, which could lead to disproportionate

increases in plasma cocaine levels in a cocaine user during binge episodes.

These findings are important in the context of cocaine toxicity among addicts

because these unexpected elevations during binge episodes could cause

severe morbidity or mortality.

Several cocaine-induced cardiovascular responses, such as elevated BP and

HR and associated increases in myocardial oxygen demand, are believed to be

mediated through the activation of the sympathetic nervous system. However,

there is no information on the relative contribution of the central nervous system

(CNS) vs. the peripheral sympathetic nervous system involved in these cocaineevoked cardiac responses. To delineate the role of these components in

cocaine-induced cardiac responses, the next group of speakers described

these responses in various animal models.

Dr. Mark Knuepfer and colleagues observed dose-dependent increases in

arterial pressure-primarily due to elevated systemic vascular resistance with

little change in cardiac output-following cocaine administration in chronically

instrumented rats. Pharmacological manipulation at ganglionic site did not

affect the cocaine-elicited peripheral vascular response; however, pretreatment

with prazosin, an alpha-adrenergic receptor blocker, did inhibit the arterial

pressure response. These findings suggest that the cardiovascular effects of

cocaine are due primarily to an action on alpha-adrenergic receptors in the

peripheral vasculature and not to CNS-mediated sympathoexcitation.

A most interesting finding of these studies is that a few animals showed

significant reduction in cardiac output after cocaine injection and a spontaneous

2
recovery from this response. Pathological findings showed focal aberrations in

the myocardium of these animals that were not observed in other animals.

These results suggest an increased sensitivity of some individuals to cocaine’s

adverse effects.

Dr. Tella and associates observed that cocaine elevated HR and BP in

conscious squirrel monkeys. These cocaine-induced increases in BP and HR

were not abolished by pretreatment with ganglionlc or alpha-adrenergic

blockers, suggesting that these responses were due primarily to cocaine’s

peripheral actions on catecholaminergic systems. They also observed unusual

cardiac responses in some monkeys following a cocaine dose. For example, an

initial reduction in HR observed in one monkey following cocaine administration

was abolished by pharmacological intervention but not in others, again

suggesting a genetic difference in the myocardium response to cocaine.

Dr. Richard Gillis and his group also observed dose-dependent increases in HR

induced by submaximal stimulation of postgangllonic cardiac sympathetic nerve

following cocaine administration in an anesthetized spinal cord-transected cat.

These results suggest a role of the peripheral sympathomimetic action of

cocaine in these responses. Further studies in cats with intravertebral

administration of cocaine revealed no significant effect on BP or HR.

Administration of cocaine methiodide, a quaternary derivative, in sedated dogs

showed cardiovascular responses similar to those of cocaine, suggesting a lack

of CNS involvement in the sympathomimetic action of cocaine.

These findings from various animal models suggesting that the

sympathomimetic effects of cocaine are due primarily to a peripheral site of

action of cocaine led to further discussions on the earlier findings of Dr.

Wilkerson and colleagues, which had shown the involvement of both central

and peripheral components of the sympathetic nervous system in these

responses in conscious dogs. These discussions can be summarized by

stating that the sympathomimetic effects evoked by cocaine depend on the

animal model used and could involve one or both components of the

sympathetic nervous system in cardiac responses.

Lethal as well as nonlethal cardiac complications associated with cocaine use

have been reported in humans. One of the frequent cardiac events reported in

young, otherwise healthy persons with angiographically normal coronary

arteries following cocaine use is acute myocardial infarction (AMI).

Mechanisms thought to be involved in this cardiac complication could be focal

vasospasm in a large epicardial coronary artery and/or diffuse increase in

coronary vascular resistance leading to a decrease in coronary blood flow in

conjunction with an imbalance between myocardial oxygen demand and supply.

3
Dr. Theodore Fraker and coworkers examined the latter mechanism in both

sedated and conscious dogs. Their studies used two-dimensional

echocardiography and showed marked, dose-dependent reductions in regional

ejection fraction following intravenous (IV) cocaine in both sedated and

conscious dogs. However, in conscious dogs the reductions in left ventricular

function were accompanied by elevationd in HR, BP, and coronary blood flow,

whereas no such hemodynamic changes were observed in pentobarbitalsedated animals. Because the cocaine-elicited depression in the left ventricular

function in sedated dogs was observed in the absence of hemodynamic

Changes, myocardial ischemia resutting from an imbalance between oxygen

supply and demand may not be responsible for the observed decline in the

myocardial function. These data also indicate that the primary mechanism most

likely involved in this response is the direct local anesthetic action of cocaine.

Dr. Koonlawee Nademanee discusses his electrophysiologicai findings in

cocaine addicts undergoing wlthdrawai and speculates on the increased risk of

these patients for developing myocardial ischemia or infarction due to possible

precipitation of coronary vasospasm during withdrawal. He observed a high

incidence of ST elevation episodes and a higher peak exercise BP in these

patients during the first week of cocaine withdrawal.

Drs. Jeffrey isner and Saurabh Chokshi examined the potential mechanism of

coronary artery vasospasm in cocaine-related AMI in one patient. Under

diagnostic coronary arteriography, this patient failed to manifest coronary

arterial spasm following cocaine injection. However, in vitro studies showed

cocaine-induced vasoconstriction in vascular tissues obtained from humans and

rabbits. Although these findings suggest an increased coronary vascular

resistance, the involvement of coronary vasospasm in cocaine-related AMI is

still speculative and tentative.

The other reported life-threatening cardiac disorder associated with cocaine use

in humans is cardiac arrhythmia and sudden death. Dr. Peter Temesy-Armos

and associates examined the underlying mechanism(s) for arrhythmia in

conscious dogs by studying continuous 24-hour ambulatory electrocardiogram

(ECG) recordings and electrophysiological changes following IV cocaine

injection. Continuous Holter recording revealed cocaine-induced ventricular

tachycardia in 5 of 12 dogs; 2 of these arrhythmias were lethal.

Electrophysiological changes seen after cocaine use suggest that both direct

and indirect actions (i.e., local anesthetic and increased sympathetic tone) of

cocaine may be involved in this cardiac complication. Because two of the dogs

had lethal arrhythmias, this again raises the question of whether a subgroup of

the population is more vulnerable to the deleterious myocardiai effects of

cocaine.

4
Dr. James Morgan and coworkers (Perreault et al., this volume) discuss the role

of intracellular calcium in the pathogenesis of cocaine cardiovascular

complications. Their in vitro studies showed that cocaine elicited both negative

and positive inotropic actions in cardiac muscle. The positive inotropic effect

appeared to be mediated by catechoiamines, whereas the negative inotropic

action probably was due to the drug’s direct local anesthetic action on

excitation-contraction coupling mechanisms. In vascular smooth muscle, a

cocaine-induced relaxant effect appeared to result from changes in myofiiament

calcium responsiveness. These physiological findings suggest that a different

mechanism may be involved with the depressant effects of cocaine on cardiac

and vascular smooth muscle.

Drs. Ronald Langner and Coilette Bement describe cocaine-induced

biochemical changes seen in blood vessels in rabbits following diet

manipulation. Cocaine administration did not produce a uniform response on

blood vessels; aortic injury was observed in some rabbits but not in others.

Rabbits sensitive to cocaine-evoked aortic injury also showed elevations in

aortic protein synthesis, cyclic adenosine monophosphate, and calcium levels,

whereas no such biochemical changes were seen in nonsensitive animals. Diet

manipulation studies showed potentiation of atherogenic processes in rabbits

fed a high cholesterol diet and cocaine. These important findings suggest that

a preexisting condition might increase the risk of premature onset of

cardiovascular complications following cocaine use.

Dr. Robert Conlee and his group describe the combined physiological and

metabolic responses of cocaine and exercise as a form of stress in an animal

model. in an exercising rat model, cocaine had a detrimental effect on

endurance and was accompanied by changes in muscle giycogen and in blood

lactic acid and catechoiamine levels. In contrast, myocardiai glycogen levels

were unaltered in these animals, suggesting that by potentiating the normal

sympathetic response during exercise, cocaine can produce adverse

consequences on performance as well as on cardiotoxic events.

Dr. Ronald Harper and colleagues discuss cocaine-induced changes on

respiratory patterning and the impact of these changes on cardiovascular

function. Cocaine administration in conscious cats produced marked elevations

in both upper airway and diaphragmatic respiratory musculature activity

accompanied by changes in cardiac rhythm, HR, and brain and core

temperature. These results suggest interaction among temperature, respiration,

and cardiovascular control systems. Another unexpected finding was the

conversion of cocaine-induced cardiac and electroencephalogram (EEG)

rhythm abnormalities seen in one cat to normal rhythm with diazepam,

suggesting that cocaine can modify neural influences on cardiac rhythm.

5
in the area of pathological findings seen at autopsy following cocaine use, Dr.

Margaret Billingham discusses the possible mechanisms for cocaine-associated

myocardiai pathological lesions, because many of these lesions have a

nonspecific etiology. For instance, the mechanism involved with cocaineassociated myocardiai contraction bands could be increased beta-adrenergic

receptor stimulation of myocytes and elevation of intracytocylic calcium or a

spasm of small vessels In the myocardium. The cause for other cocaineassociated lesions, such as myocardiai fibrosis, cardiomyopathy, and vascular

changes, may be the sympathomlmetic effect of cocaine.

Dr. Renu Vlrmani discusses the pathophysiological mechanisms involved with

cocaine-associated myocardltis. Because none of the infectious agents

associated with myocarditis etiology was found in the 40 deaths associated with

cocaine abuse, she reviews the Impact of various factors In the cause of

cocaine-related myocarditis, including cocaine-associated vasoconstrlction of

small intramyocardial coronary arteries, isolated myocyte necrosis or myocyte

death, and changes in lymphocytic activity. Dr. Virmani also discusses the

probable endotheiiai disruption and the resultant aiterations in platelet function

at the site of coronary atheroscierosis in the pathogenesis of cocaineassociated myocardial ischemia.

6
Maternal-Fetal Cardiovascular System:

A Target of Cocaine

James R. Woods, Jr., and Mark A. Plessinger

INTRODUCTION

The increasing use of cocaine by pregnant women Is affecting medical

education, clinical management, and obstetric outcome. Although obstetric

resldents In the 1970s learned to manage patients who were abusing heroin,

today’s residents are discovering firsthand the Impact of prenatal cocaine use

on the developing fetus. Hospitals that formerly could accommodate all highrisk obstetric patients In one clinic are developlng specialized high-risk clinics

for drug-dependent women to confront the ever-Increasing burdens of patient

management created by cocaine and crack abuse.

CLINICAL REPORTS OF COCAINE IN PREGNANCY

Only recently have we become aware of the significance of cocaine use In

pregnancy and its effects on the fetus. Nine years ago, a major obstetric

textbook stated that “cocaine is not known to have direct deleterious effects

upon the fetus” (Lee 1982). Since that publication, the number of case reports

concerning perinatal incidents linked to cocaine use has escalated. Acker and

coworkers (1983) reported two patients who experienced placental abruption

after their self-administration of intranasal cocaine. One of these patlents

delivered a stillborn fetus, and the other delivered a newborn that required

resuscitation. Later reports have implicated maternal cocaine abuse as the

cause of a variety of maternal and fetal complications (tables 1 and 2).

Even breast-fed newborns are not protected from maternal cocaine use, since

cocaine found in breast milk (Chasnoff et al. 1987) has been linked to neonatal

seizures and apnea (Chaney et al. 1988). Seizures in infants also have been

reported to occur when the child passively inhales freebased cocaine from an

adult’s exhaled crack smoke (Bateman and Heagarty 1980).

7
MECHANISM OF COCAINE ACTION ON REGIONAL BLOOD FLOW

In part, cocaine produces its cardiovascular effects in adults by blocking

reuptake of catecholamines within the synaptic cleft of nerve terminais (Bayorh

et al. 1093). This drug effect prolongs the actions of catecholamines at effector

terminals and also increases circulating blood levels of catecholamines (Moore

et al. 1986). The impact of these changes on the fetus is appreciable. The

uterine vasculature supplies oxygen and nutrients to the developing fetus and is

dilated throughout most of pregnancy. in the presence of elevated levels of

catecholamines, such as norepinephrine, these blood vessels constrict readily

and thereby reduce uteroplacental transfer of nutrients to the fetus.

TABLE 1. Case reports of maternal consequences of cocaine use during

pregnancy

Increased incidence of placental

hemorrhage

Chasnoff et al. 1995

Oro and Dixon 1987

Collins et al. 1989

Subarachnoid hemorrhage Lichtenfeid et al. 1984

Schwartz and Cohen 1984

lntracerebral hemorrhage Mercado et al. 1989

Premature labor Chasnoff et al. 1985

MacGregor et al. 1987

Chasnoff et al. 1989

Grand mal seizures Mercado et al. 1989

Greiss and Van Wilkes (1954) first demonstrated that the pregnant ewe is

sensitive to exogenous catecholamines. Using electromagnetic flow probes,

these investigators measured reductions in uterine blood flow during infusions

of either epinephrine or norepinephrine. Rosenfeld and West (1977) used

radiolabeled microspheres to measure a 39.3-percent reduction in uterine blood

flow in response to infusion of 0.24 μg/kg/min norepinephrine.

Later, investigators verified that cocaine, by potentiatlng the actions of

catechoiamlnes in the uterine circulation, impairs uterine blood flow and

interferes with uteroplacentai transfer of oxygen and nutrients to the fetus.

8
TABLE 2. Case reports of fetal consequences of cocaine use during

pregnancy

Prematurity

Low birth weight for gestational age

intrauterine growth retardation

Perinatal cerebral infarct

Ischemic infarct of the bowels

Genitourinary tract malformations

Cryptorchidism

Prune-belly syndrome

Hydronephrosis

Intrauterine fetal death

Abnormal neonatal

electroencephaiogram

Neurobehavioral abnormalities

in the newborn

Sudden infant death syndrome

Oro and Dixon 1987

MacGregor et al. 1987

Cherukuri et al. 1988

Chouteau et al. 1988

Chasnoff et al. 1989

Oro and Dixon 1987

MacGregor et al. 1987

Chouteau et al. 1988

Chasnoff et al. 1988

Oro and Dixon 1987

MacGregor et al. 1987

Cherukuri et al. 1988

Chasnoff et al. 1989

Chasnoff et at. 1986

Tenorio et al. 1988

Teisey et al. 1998

Chasnoff et al. 1988

Chasnoff et al. 1988

Chasnoff et al. 1988

Chasnoff et al. 1988

Critchley et al. 1988

Doberczak et al. 1988

Chasnoff et al. 1985

Doberczak et al. 1988

Chasnoff et al. 1989

Chasnoff et al. 1987

9
Mahalik and coworkers (1984) demonstrated that cocaine, when administered

to pregnant mice, reduces the transport of 22Na to the embryo. These

investigators interpreted this finding as evidence that cocaine produces

vasoconstriction of uterine blood vessels and restricts uteropiacental transfer of

the 22Na isotope. Moore and coworkers (1986) later reported that cocaine,

when glven Intravenously to pregnant ewes, increases maternal plasma

noreplnephrine and epinephrine levels and was shown to increase maternal

mean arterial blood pressure, decrease uterlne blood flow, and increase fetal

mean arterial blood pressure.

in the authors’ initial studies, cocaine was administered to pregnant ewes

(Woods et al. 1987a) to evaluate effects of intravenous (IV) cocaine on oxygen

delivery to the fetus. The results confirmed the conclusion of Mahalik and

colleagues (1984) and Moore and coworkers (1986) that cocaine produces

vasoconstriction of the uterine vasculature. Following IV administrations of 0.5,

1.0, and 2.0 mg/kg cocaine, maximum reductions of 24, 34, and 47 percent,

respectively, were observed in total uterine blood flow (figure 1). Uterine blood

flow was measured using electromagnetic flow probes.

Blood flow (Q) to the uterus is dependent on perfusion pressure (blood

pressure=BP) and resistance (R) of the uterine vascular bed In the relationship

Q=BP/R. An increase in uterine vascular resistance indicates vasoconstriction

of resistance arterioles in the uterine vascular bed. Following cocaine

administration, maximum increases of 52, 96, and 168 percent in uterine

vascular resistance were observed at the above-dose levels, respectively

(flgure 1). These findlngs indicate that cocaine produces vasoconstriction in the

uterine vasculature, and itt effects this change in a dose-related manner.

The timing of cocaine’s cardiovascular actions in the ewe and fetus provides

insight into some of the dynamic events occurring at the utero-placental-fetal

site. Following maternal cocaine administration, maximum changes in maternal

mean arterial pressure, uterine blood flow, and uterine vascular resistance

occurred within the first 5 minutes after injection (figure 1). Fetal oxygen levels,

as measured by PO2

 and O2 content, also decreased from baseline levels

within 5 minutes of maternal Injection (figure 2). These data demonstrate that

cocaine-induced vasoconstriction of the uterine vasculature reduces

uteroplacental transfer of oxygen to the fetus.

The fetal cardiovascular response to maternal cocaine injection also proved to

be a dose-dependent phenomenon. At 0.5 mg/kg cocaine, no changes in fetal

heart rate or mean arterial pressure were detected. However, a significant

increase in fetal mean arterial blood pressure was observed at the 1.0 and 2.0

mg/kg dose within 2 to 5 minutes after maternal cocaine injection (figure 3).

10
FIGURE 1.

*p<0.05

**p<0.01

***p<0.001

Responses of maternal mean arterial pressure (top), total uterine

blood flow (middle), and uterine vascular resistance (bottom) to

maternal administration of cocaine

SOURCE: Woods et al. 1987a, copyright 1987, American Medical Association.

11
FIGURE 2. Responses of fetal oxygen pressure (PO2

)(top) and fetal oxygen

(O2) con tent (bottom) to maternal administration of cocaine

*p<0.05

**p<0.01

SOURCE: Woods et al. 1987a, copyright 1987, American Medical Association.

12
FIGURE 3. Responses of fetal heart rate (top) and fetal mean arterial

pressure (bottom) to maternal administration of cocaine

*p<0.05

**p<0.01

***p<0.001

SOURCE: Woods et al. 1987a, copyright 1987, American Medical Association.

13
Fetal heart rate did not vary during the initial 5-minute period after maternal

injection. By 10 to 15 minutes after injection, however, fetal heart rate

increased dramatically in response to 1.0 and 2.0 mg/kg cocaine doses.

FETAL CARDIOVASCULAR RESPONSE TO MATERNAL COCAINE

The elevated fetal blood pressure and heart rate observed after maternal

administration of cocaine could be due to (1) the direct actions of cocaine on

the fetal cardiovascular system, (2) the resultant fetal hypoxemia from uterine

artery vasoconstriction, or (3) cocaine’s ability to potentiate the cardiovascular

actions of catecholamines released by the fetus during hypoxemia. Hypoxemia

in fetal lambs has been demonstrated to produce release of catecholamines by

fetal chromatin tissue (Phillippe 1983). Cohen and coworkers (1984)

demonstrated in near-term fetal lambs that the adrenal gland secretes primarily

norepinephrine and, to a lesser degree, epinephrine in response to hypoxemia.

Also, the secretory rates of norepinephrine and epinephrine increased with the

degree and duration of hypoxemia. These investigators also observed

Increases in fetal blood pressure during the hypoxlc episodes. Therefore,

decreases in fetal oxygen levels produce an increase in the release of

catecholamines, which elevate fetal blood pressure. Changes in fetal blood

pressure and heart rate after maternal injections of cocaine, therefore, may be

attributed to fetal hypoxemia.

To separate the indirect fetal effects of hypoxemia, via cocaine-induced uterine

artery vasoconstriction, from the direct actions of cocaine on the fetal

circulation, cocaine was injected directly into the fetal circulation (Woods et al.

1987a). Following fetal injections of 0.5, 1.0, and 2.0 mg/kg, based on

estimated fetal weight, there were no changes in maternal blood pressure, total

uterine blood flow, maternal heart rate, or maternal or fetal PO, values.

However, fetal mean arterial pressure increased rapidly after fetal

administration of cocaine, reaching a maximum value by 1 to 2 minutes after

injection. The fetal heart rate decreased during the first 2 minutes after

injection, but then increased slowly to reach a peak by 15 minutes after injection

(figure 4). These fetal heart rate and blood pressure changes were similar in

pattern to those following maternal injections. The magnitude of fetal

cardiovascular responses to direct fetal injections, however, were diminished in

comparison with those following maternal injections. The increase in fetal heart

rate and blood pressure after the maternal cocaine injection and the direct fetal

injections strongly suggests that cocaine has direct effects on fetal

cardiovascular or cardiac function that are independent of fetal oxygen levels.

Fetal hypoxemia alone produces cardiovascular effects that may provide

information regarding the effects of cocaine on the fetus. In previous studies by

14
FIGURE 4. Responses of fetal heart rate (top) and fetal mean arterial

pressure (bottom) to fetal administration of cocaine

*p<0.05

**p<0.01

***p<0.001

SOURCE: Woods et al. 1987a, copyright 1987, American Medical Association.

15
Skillman and coworkers (1985) hypoxemia was induced in fetal lambs through

the use of an externally controlled vascular clamp placed on the uterine arteries.

By this method, the authors were able to reduce total uterine blood flow to

predetermined levels while monitoring fetal oxygen levels, blood pressure, and

heart rate. Reductions in total uterine blood flow of 25 percent produced a

small drop in fetal PO2 levels (-2.4 mmHg) with no associated change in fetal

blood pressure. A 50-percent reduction in uterine blood flow produced a drop

of 7.9 mmHg in fetal PO2

 and an increase of 5 mmHg in fetal blood pressure.

A 83-percent reduction in total uterine blood flow produced a decrease of 8.2

mmHg in fetal PO2 and an increase of 5 mmHg in fetal blood pressure.

Although catecholamine release was not monitored in this study, there appears

to be a direct relationship between the degree of fetal hypoxemia and fetal

cardiovascular response.

A comparison of fetal cardiovascular changes obtained during mechanical

reductions in uterine blood flow with those following maternally administered

cocaine provides additional evidence that the two methods for producing

reduced uterine blood flow differ in their effects on the fetus. Total uterine blood

flow was reduced by 24, 34, and 47 percent when maternal cocaine was given

at 0.5, 1.0, and 2.0 mg/kg, respectively. Mechanical reduction in uterine blood

flow of 50 percent approximates the 47-percent reduction in uterine blood flow

observed after the 2.0 mg/kg cocaine dose. Despite similar drops in fetal PO2

in response to the two techniques, the increase in fetal blood pressure following

maternal cocaine administration was approximately twice that following

hypoxemia via vascular clamping (50 percent) of uterine arteries, This

difference suggests that cocaine, which crosses the placenta to the fetus,

potentiates the cardiovascular actions of fetal catecholamines or increases their

release during hypoxemia via uterine vasoconstriction.

PLACENTAL PASSAGE OF COCAINE TO THE FETUS

Drugs such as cocaine that are highly soluble in lipids and aqueous solutions

generally pass easily from the maternal to the fetal circulation. Moore and

coworkers (1986) measured maternal plasma cocaine levels in response to

three doses of cocaine (0.3, 0.5, and 1.0 mg/kg) and fetal plasma cocaine

levels in response to one dose of cocaine (0.5 mg/kg). These investigators

observed that, within 5 minutes following maternal injection of 0.5 mg/kg, fetal

plasma cocaine levels were approximately 12 percent of the maternal plasma

cocaine levels. In a later study, Woods and coworkers (1989) examined

maternal and fetal serum cocaine levels in response to 1.0 and 2.0 mg/kg

maternal cocaine administration. Woods and colleagues (1989) showed fetal

serum cocaine levels of 14 and 17 percent of maternal serum levels at 5

18
minutes following maternal cocaine injection of 1.0 and 2.0 mg/kg, respectively.

Although at these two doses, uterine artery vasoconstriction was dosedependent, these data suggest that placental transfer of cocaine to the fetus is

not limited by cocaine-induced uterine artery vasoconstriction.

In a separate experiment, maternal blood samples were taken every 30

seconds for the first 15 minutes and at 30 and 60 minutes following maternal

cocaine administration of 2.0 mg/kg. Fetal blood samples also were taken

every 30 seconds for the first 5 minutes, then every minute for 15 minutes, and

then at 30 and 80 minutes. Maternal cocaine levels were maximum at the first

30-second sample, declined rapidly until 5 minutes (figure 5), then declined

FIGURE 5. Maternal and fetal serum cocaine levels in one experiment

obtained every 30 seconds to 1 minute for 15 minutes and then at

30 and 60 minutes following IV injection of cocaine, 2.0 mg/kg

SOURCE: Woods et al. 1989, copyright 1989, New York Academy of Sciences.

17
slowly to near zero levels by 80 minutes after injection. Fetal cocaine levels

initially increased to peak by 2 minutes after injection and coincided with

maximal increases in fetal mean arterial pressure. Thereafter, the fetal cocaine

levels declined rapidly from 4 to 6 minutes after injection, remained at low levels

to 30 minutes, and were undetectable by 60 minutes. These data demonstrate

that cocaine neither equilibrates nor accumulates in the fetal blood

compartment. Moreover, the fetus appears to have the capacity to metabolize

cocaine, or the cocaine is distributed into other fetal tissues. It is noteworthy

that fetal cocaine levels remained relatively constant from 6 to 30 minutes after

maternal administration, despite recovery of uterine blood flow to approximate

control values by 10 minutes after cocaine injection. That there was no

increase in fetal cocaine levels during this period of uterine blood flow

restoration suggests either that once maternal cocaine concentrations drop

below a certain level, there is no further placental transfer of cocaine to the

fetus or that the fetus has the capacity to metabolize or redistribute to its tissues

the additional cocaine transferred during uterine blood flow restoration.

ROLE OF ALPHA-ADRENERGIC RECEPTORS IN COCAINE-INDUCED

UTERINE ARTERY VASOCONSTRICTION

Blood vessel vasoconstriction occurs primarily by the interaction of

norepinephrine with alpha-1-adrenergic receptors. The uterine resistance

arterioles possess alpha-receptors that produce vasownstriction of the uterine

vasculature when stimulated. If the primary mechanism by which cocaine

produces its vasoconstrictlve action on the uterine vasculature is mediated by

alpha receptors, then the vasoconstrictive effects of cocaine should be blocked

by an alpha-l receptor blocking agent.

Phenoxybenzamine, a noncompetitive alpha-1 receptor blocking agent, was

employed to determine whether uterine vasoconstrictive actions of cocaine

could be blocked (Dolkart et al. 1990). Pretreatment with phenoxybenzamlne

5.0 μg/kg blocked increases in blood pressure or uterine blood flow following IV

doses of norepinephrine, 30 mg, in pregnant ewes. Administration of 2.0 mg/kg

cocaine in pregnant ewes before phenoxybenzamine produced a 53-percent

increase in maternal mean arterial pressure, a 50-percent reduction in uterine

blood flow, and a 191 -percent increase in uterine vascular resistance. After

phenoxybenzamine administration, there was no increase in maternal mean

arterial pressure in response to a second dose of cocaine. However, there was

a 44-percent reduction in uterine blood flow and a 59-percent increase in

uterine vascular resistance. These data indicate that vasoconstriction of the

uterine vascular bed occurs in response to cocaine despite complete uterine

and systemic alpha-1 receptor blockade. Thus, cocaine acts on the uterine

vasculature by other mechanisms in addition to alpha-adrenergic receptor

stimulation.

18
The fetal response to maternal cocaine injection during alpha-adrenerglc

blockade confirmed that uterine artery vasownstriction had occurred. Before

phenoxybenzamine administration, cocaine produced a 24-percent increase in

fetal mean arterial pressure, a 51 -percent increase in fetal heart rate, and a 29-

percent reduction in fetal PO2 levels. After phenoxybenzamine, there was no

increase in fetal mean arterial pressure; however, fetal heart rate increased 38

percent, and fetal PO2

 decreased 18 percent. Not only did the reductions in

fetal PO2 levels in response to cocaine after phenoxybenzamine confirm that

uterine artery vasoconstriction had occurred, but also the lack of increase in

fetal mean arterial pressure indicated that phenoxybenzamine had crossed the

placenta to block fetal alpha-1 receptors as well.

COMPARISON OF COCAINE’S CARDIOVASCULAR ACTION IN THE

PREGNANT AND NONPREGNANT EWE

Changes in cardiac output, blood volume, receptor function, and hormonal

levels are known to occur during pregnancy. To evaluate the influence of these

pregnancy-related changes on cocaine’s actions, the responses of blood

pressure and heart rate to cocaine were measured in nonpregnant

oophorectomized ewes and pregnant ewes. In response to cocaine in doses of

1.0 and 2.0 mg/kg, pregnant ewes exhibited a twofold greater increase in

systolic blood pressure, diastolic blood pressure, and mean arterial pressure

(Woods and Plessinger 1990) than did nonpregnant ewes. These results were

surprising, because many drugs produce lesser cardiovascular effects during

pregnancy (Perucca 1987). This increased sensitivity of pregnant ewes Is

attributed to possible changes in cocaine metabolism, increases in peripheral

adrenergic sensitivity to norepinephrine, or differences in cocaine-induced

cardiac responsiveness.

Cocaine (benzoylmethylecgonine) is a methyl ester that is metabolized by liver

and plasma esterases and cytochrome P450 enzymes. In a study by Stewart

and coworkers (1978), cocaine given to rats was found to be metabolized by Ndemethylation to norcocaine at a rate of 20 percent of the cocaine dose.

Norcocaine is a potent local anesthetic agent that inhibits norepinephrine

reuptake by the presynaptic membrane to a greater degree than does cocaine

(Hawks et al. 1974). The remaining metabolism (80 percent) of cocaine

appears to be mediated by plasma and liver esterases and microsomal

monooxygenase (Stewart et al. 1979). The increased sensitivity of the pregnant

ewe to cocaine may be due to a reduced metabolism of cocaine or to an

increase in bioactivation of cocaine to norcocaine. Reports have indicated that

there are reductions in liver cytochrome P450 concentrations (-25 percent) and

reduced activities of glucuronyl transferase (Neale and Parke 1973) and

monooxygenase (Dean and Stock 1975) in pregnant rats and rabbits.

19
Aminopyrine is an agent that is commonly used as a substrate in studies of

microsomal monooxygenases, most notably N-demethylation reactions.

Because progesterone treatment of nonpregnant rats is known to produce an

increase in N-demethylation of aminopyrine (Ochs et al. 1986), high levels of

progesterone in the pregnant ewes also may produce an increase In Ndemethylation of cocaine to norcocaine. This hypothesis is especially plausible

since Stewart and coworkers (1978) demonstrated that N-demethylation of

cocaine to norcocaine has kinetics that are nearly identical to those for Ndemethylation of aminopyrine.

Alpha-adrenergic receptor sensitivity also may increase during pregnancy,

producing the observed increase in blood pressure response to cocaine in

pregnant ewes. if, during pregnancy, alpha-1 receptor sensitivity to

norepinephrine increased, this change could explain the greater increase in

blood pressure observed in pregnant ewes than in nonpregnant ewes.

McLaughlin and coworkers (1985) used phenylephrine, an alpha-1 agonist, to

demonstrate that vascular reactivity of the hind limb to this agent increased

following treatment of nonpregnant ewes with progesterone. In this study, the

vascular reactivity of the hind limb of pregnant ewes also was found to increase

in comparison with that observed in untreated nonpregnant ewes. Other

investigators have reported that estrogens increase the number of adrenergic

receptors (Peters et al. 1979). Collectively, these observations indicate that

pregnancy produces an increased peripheral reactivity to exogenous or

endogenous norepinephrine, and pregnancy hormones may explain the

increased cardiovascular responsiveness seen in pregnant ewes exposed to

cocaine.

HORMONAL ROLE IN PREGNANCY-RELATED COCAINE ACTION

To determine whether pregnancy-related alterations in hormonal levels are

responsible for increased sensitivity of pregnant ewes to cocaine, responses of

blood pressure and heart rate in nonpregnant oophorectomized ewes to

cocaine were examined before and during 3 days of treatment with

progesterone (Woods et al. 1987b, 1988; Plessinger and Woods 1990). in

addition, blood pressure responses to norepinephrine were examined In these

animals to determine whether alpha-adrenergic receptor sensitivity was

influenced by progesterone. Responses of systolic blood pressure, diastolic

blood pressure, mean arterial pressure, pulse pressure, and heart rate to

norepinephrine were similar before and during 3 days of progesterone

treatment. These consistent responses Indicated that progesterone has no

influence on and does not alter alpha-1 receptor sensitivity to norepinephrine.

in contrast, blood pressure increases in response to cocaine at either 1.0 or 2.0

mg/kg were approximately two times greater during each day of progesterone

20
treatment when compared with the responses of nonpregnant ewes to the same

dose of cocaine before progesterone. Increased sensitivity to cocaine was

consistent throughout all 3 days of progesterone treatment. These data

indicate that progesterone increases cardiovascular responses to cocaine.

Alterations in alpha-1 receptor sensitivity, however, do not seem to explain this

phenomenon.

Progesterone may produce an increased cardiac sensitivity to cocaine, leading

to increased cardiac output as an explanation for the elevated blood pressure

seen in pregnant ewes and progesterone-treated nonpregnant ewes. If so,

progesterone may potentiate the action of cocaine to increase heart rate or

cardiac contractility. From in vivo preparations, there is evidence that cocaine

may act directly on the heart. Mugge and coworkers (1984) used isolated cat

papillary muscle strips to examine the force of cardiac contraction in response

to phenylephrine in the presence of cocaine and hydrocortisone, a

corticosteroid. Cocaine alone increased the force of contraction, and

pretreatment with hydrocortisone increased this cocaine effect even further.

Although these investigators were interested mainly in extraneuronal uptake of

phenylephrlne, which is inhibited by hydrocortisone, their data illustrate that

steroids have an influence on cardiac contractility and can potentiate effects of

cocaine.

COCAINE EFFECTS ON NEUROBEHAVIOR AND CARDIOPULMONARY

FUNCTION

Although most of the authors’ studies to date have used 1.0 and 2.0 mg/kg

doses in pregnant ewes, they have expanded the dosage regimen to include

3.0 and 5.0 mg/kg. At these doses, cocaine in pregnant ewes produced

placental abruptions, cardiac arrhythmias, respiratory distress, seizures, and

death (Woods et al. 1989) (table 3). in the nonpregnant ewe, increasing the

dose of cocaine to 3.0 or 5.0 mg/kg only increased the hypertensive response

in a dose-dependent manner. Not until doses of 10.0 to 15.0 mg/kg were

administered to nonpregnant ewes were the sequelae of cardiac arrhythmias,

respiratory distress, seizures, and death observed. These results indicate that

there is a shift to the left in the cocaine dose-response curve for cardiovascular

as well as neurobehaviorai and lethal sequelae in the pregnant ewe. These

data strongly suggest that pregnancy increases the risk of cocaine-induced

cardiovascular and neurologic complications and death.

The seizure activity exhibited by pregnant and nonpregnant ewes is

characterized by extension of the extremities, collapse, opisthotonos, and

respiratory distress. These observations indicate that cocaine, at least in the

ewe, produces strychnine-type seizures. The convulsive actions of strychnine

21
reportedly result from alterations in glycine metabolism. As a result, inhibitory

influences on nerve impulses are blocked and movement at any given joint is

manifested by contraction of the strongest muscle at that joint. This results in

dramatic arching of the back and neck (opisthotonos), extension of all

extremities, and spasm of the diaphragmatic muscles leading to respiratory

distress (Franz 1985). That cocaine produces strychnine-like seizures suggests

that cocaine in high doses may selectively block inhibitory neurons.

TABLE 3. Cocaine responses in the pregnant ewe

IV Dose (mg/kg) N

0.5 5

Responses

No restlessness, no arrhythmias

1.0-2.0 15 Increased restlessness, vocalization (15/1 5);

increased attentiveness (15/15); mild

arrhythmias

3.0 5 Acute myocarditis (1); pulmonary artery

rupture (1); abruptio placenta (1)

5.0 3 Seizure activity and opisthotonos (3/3);

death by arrhythmias (1/3);

respiratory distress (3/3)

SOURCE: Woods et al. 1989, copyright 1989, New York Academy of Sciences.

USING ANIMAL STUDIES TO EXAMINE DRUG CONSEQUENCES

IN HUMANS

One of the difficulties with using animal models for the study of any drug is the

extrapolation of these results to humans. Few controlled studies of effects of

cocaine on humans have been reported in the literature. Furthermore,

uncertain purity of “street” cocaine and estimation of amount of cocaine

consumed make it impossible to establish a relationship between dose and

clinical complication. Based on autopsy results of cocaine overdose victims, the

lethal dose of cocaine in the human is estimated to be 1.4 g (Smart and Anglin

1987), which is approximately 20 mg/kg for a 70 kg individual. This estimation

of human lethal cocaine dose approximates the lethal dose that the authors

have observed for nonpregnant ewes. Sheep, therefore, appear to be doseappropriate animal models for cardiovascular studies when compared with

22
rodent models. The lethal dose of cocaine in rats by intraarterial injection is 148

mg/kg (Nahas et al. 1985). Selection of an appropriate animal model for studies

of cocaine is crucial if we are to understand the effects of cocaine on the fetus.

CONCLUSION

Collective data generated in animal models help explain some of the clinical

consequences of cocaine use by pregnant women. The rapid onset of maternal

hypertension following IV administration of cocaine may be responsible for

placental abruptions, subarachnoid hemorrhage, intracerebrai hemorrhage, and

onset of premature labor. Uterine artery vasoconstriction may interfere with

placental transfer of oxygen and essential nutrients necessary for fetal growth

and development. The observation that cocaine produces reduced uterine

blood flow and increased uterine vascular resistance (vasoconstriction) may

help explain the observed incidence of fetal growth retardation and low birth

weights in babies exposed to prenatal cocaine. The fetal hypertensive effects

of cocaine observed following direct fetal injectlons of cocaine were, In part,

independent of hypoxia and may explain cocaine-related intrauterine cerebral

and bowel infarcts. Abnormal neurobehavioral effects seen in newborns may

be the result of cocaine-induced fetal hypoxia, or they may be secondary to

direct effects of cocaine and its metabolites.

One of the most confounding variables in linking human and animal studies of

cocaine is that typical cocaine abusers use several other drugs in conjunction

with cocaine. Some of the cocaine-related events observed in pregnant

cocaine addicts may result from interactions of cocaine with other abused

drugs. Nevertheless, animal studies certainly indicate that cocaine has the

potential to be damaging to the woman and her fetus.

A second reason for cautiously extrapolating animal data to humans is the

possibility that interspecies differences in cocaine responses may exist. Among

case reports that have been published to date, there are no reports that indicate

that pregnant women are more sensitive to cocaine than are nonpregnant

women, even though the authors’ results in pregnant and nonpregnant ewes

clearly demonstrate this phenomenon. In addition, the data reported in their

studies were generated from pregnant and nonpregnant ewes exposed to

cocaine for the first time. The typical abuser has used cocaine repeatedly

before conception and, in many cases, continues to use the drug repeatedly

throughout pregnancy. The effects of long-term chronic cocaine exposure on

the pregnant ewe and her fetus therefore remain to be investigated.

23
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ACKNOWLEDGMENT

This work is supported by National lnstitute on Drug Abuse grant DA-04415.

AUTHORS

James R. Woods, Jr., M.D.

Director

Obstetrics and Maternal Fetal Medicine

Mark A. Plessinger, M.S.

Senior Technical Associate

Department of Obstetrics and Gynecology

Strong Memorial Hospital

University of Rochester Medical Center

Box 668

601 Elmwood Avenue

Rochester, NY 14642

27
Pharmacokinetics and Time-Action

Profile of Cocaine in Dogs

R. Douglas Wilkerson, Peter N. Temesy-Armos, and

Theodore D. Fraker, Jr.

INTRODUCTION

A fundamental principle of drug action is that the magnitude of the drug

response is a function of its concentration at its site(s) of action. Although

tolerance (Fischman et al. 1985; Chow et al. 1985) and sensitization (Downs

and Eddy 1932a, 1932b) have been reported after cocaine treatment, these

phenomena modify the relationship between drug concentration and effect; they

do not negate the above principle. Many drugs exert more than one

pharmacologic action and generally exhibit different concentration-response

relationships for individual actions. For example, cocaine exerts at least two

pharmacologic actions-inhibition of neuronal monoamine transport

(Trendelenburg 1959) and local anesthesia (Ritchie and Greene 1990)—and

these two actions have different concentration-response relationships, with the

former occurring at much lower concentrations than the latter (Yasuda et al.

1984).

Because the concentration of a drug at its active site(s) rarely can be

determined, the concentration of drugs in plasma or serum generally is

employed in attempts to define concentration-response relationships. Although

not ideal, this approach has several advantages over the use of the dose

administered to infer relationships between the quantity of drug and its effect

(Neubig 1990). indeed, it is only that fraction of the quantity administered that

exists unbound in arterial plasma perfusing the area in which a drug acts that is

available to diffuse out of the circulation and possibly reach its site of action.

The dose of a drug is one of the major determinants of plasma drug

concentration. Indeed, it is the only determinant that can be selected by the

investigator. Probably for this reason and to avoid the necessity for difficult and

expensive analytical procedures, it is used frequently instead of plasma drug

concentration in quantitative expressions of the relationship between the effect

of a drug and the amount of the drug available to produce that action. In fact,

the plasma drug concentration, or more precisely, the plasma concentration of

28
unbound drug, is a much better indicator of the drug concentration at its site of

action than is the total dose administered. This is because unless a drug Is

administered intravenously, several factors in addition to the dose influence its

concentration in plasma and, thus, at its site of action.

One of these factors is the bioavailability of the drug, which is defined as that

fraction of the dose administered that reaches the arterial side of the circulation

and, thus, may reach the site of action. Only Intravenous (IV) administration

guarantees 100 percent bioavailability. Any route of administration that

exposes cocaine to the action of esterases before reaching the arterial side of

the circulation may result in low and/or unpredictable bioavailablllty (Stewart et

al. 1977, 1979). Although cocaine is effective after oral administration (Jatlow

1988; Van Dyke et al. 1978), it virtually never is administered orally because of

the potential for poor bioavailability by this route. The intraperitoneal (IP) route

of administration, however, is used frequently in rodent species. Unfortunately,

even though this is a parenteral route that provides a large absorptive surface

allowing relatively rapid absorption, the absorption is largely into the hepatic

portal circulation, which exposes cocaine to the same hepatic clearance

mechanisms as after oral administration (Benet et al. 1990). Another factor that

influences the plasma concentration of a drug is its rate of absorption. Although

the IV route provides instantaneous absorption into the vascular compartment,

all other routes impose barriers that the drug must cross to reach the circulation.

Two major factors that Influence the rate of absorption from any site of

administration are the rate of blood flow to that site and the surface area over

which absorption may occur. Because of its action to cause peripheral

vasoconstriction, cocaine may reduce its own rate of absorption when

administered by non-IV parenteral routes. Finally, the rate of elimination of

active drug is probably the major factor determining the plasma concentrationtime relationship for any drug. Thus, because of the complex factors involved in

the absorptive process after non-IV administration, it is probably not appropriate

to assume that the same relationship always exists between the dose

administered and cocaine plasma concentration. There is undoubtedly

considerable variation between animals and possibly even from one dose to the

next in the same animal.

Even when cocaine is administered intravenously, one cannot assume that the

same dose always will result in the same plasma cocaine concentration-time

profile. The rate of IV administration is a major determinant of the plasma

cocaine concentration-time relationship. Thus, the same IV cocaine dose

administered over a 10- to 15-second period will result in a much higher peak

plasma cocaine concentration than when administered over a 1 -minute period,

even though the areas under the plasma concentration-time curves may be

equivalent. A continuous IV infusion will result in an even slower approach to a

29
maximum (and in this case steady-state) plasma concentration, which will be

achieved after a time equivalent to 4- to 5-elimination half-lives, if cocaine does

not accumulate to a lethal level before reaching the plateau concentration

dictated by the infusion rate chosen and its rate of clearance from the animal.

Consequently, the time-action profile of the same IV cocaine dose may vary

considerably, depending on the rate of IV administration. Thus, it is important to

understand the influence of these factors if research in laboratory animals is to

produce findings relevant to Its effects in humans.

EXPERIMENTAL MODEL

To gain a better understanding of the plasma concentration-time relationship

and the plasma concentration-effect relationship for cocaine after IV

administration, we administered cocaine to chronically instrumented conscious

dogs, a model we have described elsewhere (Wilkerson 1988). Briefly, dogs

were trained to stand quietly in a nylon sling during cardiovascular monitoring.

After training, cardiovascular monitoring devices were implanted in each animal.

These devices included a doppier blood flow transducer that was implanted

around the left circumflex coronary artery and an electromagnetic blood flow

transducer that was implanted around the root of the aorta. Wires from these

devices and subcutaneous electrocardiogram (ECG) electrodes were

exteriorized to the animal’s back. In addition, catheters were implanted in an

omocervical artery and an omocervicai vein for blood pressure recording and

drug administration or blood withdrawal, respectively. These catheters also

were exteriorized to the back of the animal’s neck. All surgical procedures were

performed under sterile conditions, and animals received preoperative and

postoperative prophylactic antibiotic treatment. In addition, morphine was

administered postoperatively to prevent pain or discomfort.

Throughout an animal’s participation in these studies, all cutaneous incisions

were treated daily with antibiotic ointment and covered with sterile bandages,

except when standing in the nylon sling during an experiment. A soft leather

collar was utilized to protect the catheters, and a cotton body stocking covered

by a nylon jacket was utilized to protect flow transducer and ECG wires.

Dressings were changed dally, and catheters were flushed and filled with

heparinized saline daily. Sterile procedures were observed for drug injections

and blood withdrawal during ail experiments. in all experiments, cocaine was

administered intravenously with the entire dose being given over a 10- to 15-

second period. With the exception of six animals that received chronic cocaine

treatment for a 4-week period, no animal received more than one dose of

cocaine during each experiment, and the interval between experiments was at

least 48 hours. The six animals receiving chronic cocaine treatment were given

2 mg/kg twice daily for 4 weeks. On the last day of chronic cocaine treatment, 4

30
mg/kg was administered as a single dose to determine the plasma

concentration-time profile for cocaine.

PHARMACOKINETICS OF COCAINE IN THE DOG

The plasma concentration-time profile for cocaine was studied after IV

administration of three doses of cocaine in chronically instrumented, conscious

dogs. Animals that previously had not received cocaine treatment were given

either 1, 2, or 4 mg/kg doses of cocaine intravenously as described above.

Blood samples (5 mL) were obtained 1, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120,

and 160 minutes after each dose. Samples were placed immediately into tubes

containing sodium fluoride (to Inhibit plasma esterase activity) and heparin and

centrifuged. After centrifugation, plasma was collected and frozen at -40°C until

assayed. Plasma cocaine concentration was determined by the Medical

College Hospital Toxicology Laboratory using a modification of the gas

chromatography-mass spectroscopic procedure described previously (Foltz et

al. 1980). Deuterated cocaine (0.25 mg/L) and deuterated benzoylecgonine

(0.25 mg/L) were added to each sample as internal standards. The sensitivity

of this assay for cocaine is 0.02 mg/L, and it is linear over a range of 0.02 to

10.0 mg/L.

Figure 1 illustrates the plasma concentration-time relationship for each of the

three doses of cocaine in this experimental model. The peak plasma cocaine

concentrations, observed 1 minute after administration of 1, 2, and 4 mg/kg of

cocaine, were 0.92±0.07 mg/L, 2.1±0.6 mg/L, and 3.48±0.26 mg/L, respectively.

Plasma cocaine concentrations 1 hour after administration of the above doses

were 0.097±0.013 mg/L, 0.21±0.02 mg/L, and 0.44±0.03 mg/L, respectively.

Pharmacokinetic analysis of the data presented in figure 1 was performed using

PCNONLIN (Statistical Consultants, Inc., Lexington, KY), a software package

designed for statistical analysis of general nonlinear models, including

pharmacokinetic models. Although distribution of cocaine after a single IV dose

is rapid, a two-compartment open model was employed for the pharmacokinetlc

analysis of the cocaine plasma concentration-time data obtained in these

experiments (Neubig 1990). Although a one-compartment model has been

used to analyze cocaine pharmacoklnetics (Wilkinson et al. 1980), a twocompartment model provides a more rigorous analysis and has been shown to

better fit cocaine disposition in humans (Chow et al. 1985; Ambre 1986).

The pharmacokinetic parameters calculated for the three cocaine doses are

shown in table 1. No significant differences were noted between the 1 and 2

31
FIGURE 1. Plasma concentration of cocaine as a function of time after

administration for IV doses of 1 mg/kg (squares), 2 mg/kg

(triangles), and 4 mg/kg (circles) in chronically instrumented

conscious dogs

NOTE: Points represent the mean±SEM for seven animals at the 1 mg/kg dose

and nine animals each at the 2 mg/kg and 4 mg/kg doses.

mg/kg doses except that the area under the plasma concentration vs. time

curve increased as a function of dose after the 2 mg/kg dose. Cocaine

distribution was rapid and occurred with a half-life of less than 3 minutes. The

elimination half-life for cocaine was approximately 29 minutes after

administration of each dose. Previous studies have reported that the

elimination half-life of cocaine in humans ranged from 15 minutes to

approximately 1.5 hours (Chow et al. 1985; Wilkinson et al. 1980; Javaid et al.

1976; lnaba 1989; Barnett et al. 1981); it was reported to be 18 minutes in rats

(Misra 1976) and 16 minutes in mice (Benuck et al. 1987).

Thus, the rate of elimination of cocaine in the dog appears to be quantitatively

similar to humans. Although several studies have reported elimination half-lives

for cocaine that were different for different routes of administration (e.g.,

subcutaneous vs. IP), these differences probably resulted from methodological

problems rather than differences in the rate of elimination of cocaine from

plasma. Although, as stated above, the character of the plasma concentration32
time relationship may be markedly different for the same dose given by different

routes of administration, the elimination half-life for any drug is independent of

absorptive processes when correctly determined. Undoubtedly, studies that

report elimination half-lives for cocaine that are different for various routes of

administration have not restricted their analysis to the slope of the terminal

phase of the plasma concentration-time curve but have incorrectly mixed data

from the absorption and elimination phases in their analysis.

TABLE 1. Cocaine pharmacokinetics

Acute Cocaine Treatment Only Intravenous Cocaine Dose (mg/kg)

1 2 4

(N=7) (N=9) (N=9)

Distribution half-life (min) 2.52±0.76 2.40±0.56 3.81±0.65

Elimination half-life (min) 29.29±5.20 29.23±2.38 47.02±4.74

Apparent volume of distribution 0.78±0.18 1.22±0.21 1.07±0.11

(L/kg)

Area under plasma concentration 17.89±1.63 30.53±3.04 97.09±7.24

vs. time curve (mg/L*min)

Total body clearance

(mL/min/kg)

60.35±7.10 71.73±7.35 33.85±4.50

These relationships between the 1 and 2 mg/kg doses would be expected for a

drug that is eliminated by first-order processes. On the other hand, there were

significant differences in the pharmacoklnetics of cocaine after the 4 mg/kg

dose. The total body clearance of cocaine was decreased by approximately 50

percent after the 4 mg/kg dose compared with the 1 and 2 mg/kg doses, This

resulted in a significant increase in the elimination half-life after the 4 mg/kg

dose. Similarly, the area under the plasma concentration vs. time curve, which

should be linearly related to dose if cocaine elimination continued to be by a

first-order process, was significantly more than doubled when the dose was

increased from 2 mg/kg to 4 mg/kg. These data clearly indicate that cocaine

elimination in the dog becomes saturable somewhere between 2 mg/kg and 4

mg/kg, that is, between peak plasma cocaine concentrations of approximately 2

mg/L and 3.5 mg/L. At this higher concentration of cocaine, additional

increments in cocaine dose would be expected to result in much greater than

anticipated increments in plasma concentration. Most studies of the

pharmacokinetics of cocaine in humans have reported a linear relationship

33
between cocaine dose and cocaine plasma concentration, suggesting

elimination solely by processes that were independent of cocaine plasma

concentration (Wilkinson et al. 1980; Van Dyke et al. 1977); however, Barnett

and colleagues (1981) reported two patients who exhibited concentrationdependent elimination kinetics for cocaine. Similarly, concentration-dependent

elimination kinetics recently have been reported for cocaine in sheep (Khan et

al. 1987).

The paucity of reports of concentration-dependent elimination kinetics for

cocaine in human subjects may be the result of prudent selection of cocaine

doses in human study subjects to minimize risk in those individuals. At the

relatively low doses employed in these studies, the plasma concentration of

cocaine may be well below that required to begin to saturate elimination

processes, which must occur before concentration-dependent elimination

kinetics can be detected. On the other hand, individuals who abuse cocaine

frequently administer multiple doses of cocaine at intervals that should result in

cocaine plasma concentrations far in excess of those obtained during studies

on human volunteers where cocaine doses are controlled by the investigator.

A concern with any drug such as cocaine that is used chronically is whether

chronic use leads to changes in the way the drug is handled by the body. To

address this question in our animal model, we compared the plasma

concentration-time relationships for single 4 mg/kg IV doses of cocaine in dogs

that had received no previous cocaine treatment and dogs that had received

chronic cocaine treatment for 4 weeks (2 mg/kg twice daily). Figure 2 shows

the plasma cocaine concentration-time relationships for these two groups of

animals, No significant effect of chronic cocaine treatment was observed in

these studies,

TIME-ACTION PROFILE FOR COCAINE IN CONSCIOUS DOGS

Nine chronically instrumented conscious dogs that had been trained to stand

quietly in a nylon mesh sling for extended periods were treated with cocaine, 2

mg/kg IV, during continuous recording of blood pressure, heart rate, left

circumflex coronary artery blood flow, and cardiac output (aortic blood flow). At

times corresponding to those employed in pharmacokinetic studies described

above, blood samples were obtained for determination of plasma cocaine

concentration. Before cocaine administration and 5, 30, 60, and 120 minutes

after cocaine treatment, norepinephrine, 0.25 μg/kg IV, was administered. The

duration of the increase in blood pressure was determined after each

norepinephrine treatment and was employed as an index of neuronal

monoamine transport function. Because neuronal monoamine uptake is the

major mechanism by which the action of norepinephrine is terminated (Iversen

34
FIGURE 2. Effect of chronic cocaine treatment on the pharmacokinetics of a

single 4 mg/kg IV cocaine dose in chronically instrumented

conscious dogs. Plasma cocaine concentrations after the 4 mg/

kg IV bolus of cocaine in 17 naive animals are shown by circles,

and those concentrations after the same cocaine dose given to 6

animals on the 28th day of chronic cocaine treatment (2 mg/kg IV

twice daiiy) are shown by triangles.

NOTE: Each point represents the mean±SEM.

1975), inhibition of that transport increases the duration of action of

norepinephrine.

Figure 3 illustrates the effects of cocaine on the above cardiovascular

parameters. Immediately after administration of cocaine, blood pressure, heart

rate, and coronary blood flow are significantly increased. Although the change

in heart rate ceases to be significant within 5 minutes after cocaine treatment,

blood pressure and coronary blood flow remaln significantly elevated for an

hour after this single dose of cocaine. Cardiac output was not changed

significantly at any time after cocaine treatment. It is interesting to note that

the effects of cocaine on blood pressure roughly parallel plasma cocaine

concentration; it is undoubtedly the increase in myocardial oxygen demand

imposed by this increase in blood pressure that keeps coronary blood flow

elevated along with blood pressure. Of particular interest is the relationship

35
FIGURE 3. Time-action profile for cocaine after a 2 mg/kg IV dose in

chronically instrumented conscious dogs. The dotted curve

represents the mean cocaine plasma concentration at each time

that is plotted against the left ordinate. Cardiovascular responses

to cocaine are plotted as percent change from their pretreatment

value against the right ordinate. Mean arterial blood pressure is

shown as open circles; heart rate is shown as closed circles;

coronary blood flow is shown as closed, upward pointing

triangles; cardiac output is shown as open squares; and the

duration of the pressor response to norepinephrine, 0.25 mg/kg

IV, is shown as the closed, downward pointing triangles.

NOTE: All points represent the mean±SEM for nine animals.

between the cardiovascular effects of cocaine and its action to inhibit neuronal

monoamine transport. Although the cardiovascular changes elicited by the

2 mg/kg dose of cocaine dissipated within 60 to 90 minutes after treatment,

neuronal monoamine transport appears to be significantly inhibited 120

minutes after cocaine treatment. This is indicated by our finding that the

duration of the pressor response to 0.25 μg/kg of norepinephrine remained

significantly longer than that observed before to cocaine treatment.

38
POTENTIAL IMPLICATIONS OF THESE FINDINGS

A major complicating factor in any attempt to relate cocaine dose to plasma

concentration and pharmacologic effect is the flndlng that, at high plasma

concentrations, cocaine elimination processes become saturated and its

elimination ceases to be a first-order process. Thus, additional dose increments

result in much larger than expected increments in plasma concentration. This

fact alone may be a major contributing factor to cocaine toxicity among users.

When cocaine is used in binges, individual doses that produce modest

increments in the plasma cocaine concentration at the beginning of the binge

may result in much larger increments at a time when the plasma cocaine

concentration is still elevated from previous doses. Thus, if tolerance develops

to the central stimulant actions of cocaine, the added dose increments required

to maintain the desired high may push the plasma cocaine concentration into

the range where its elimination processes become saturated, thus setting the

stage for subsequent doses to produce unexpectedly large increments in

plasma concentration and lead to toxicity. This is an especially dangerous

situation with cocaine, because tolerance probably does not develop to its local

anesthetic actions, which are characterized by a concentration-response

relationship that is approximately one log unit higher on the concentration axis

than the actions of cocaine to inhibit monoamine uptake (Yasuda et al. 1984). it

also is not clear whether tolerance develops to the other cardiovascular actions

of cocaine. Although tolerance to the increase in heart rate elicited by cocaine

has been reported to occur (Fischman et al. 1985; Chow et al. 1985; Ambre et

al. 1988), this finding has not been universal (Kumor et al. 1988). No tolerance

has been observed to the actions of cocaine that result in increased blood

pressure (Kumor et al. 1988; Foltin et al. 1988). Thus, cardiovascular toxicity

associated with these adrenerglc actions of cocaine as well as its local

anesthetic effects may be a direct result of nonlinear pharmacokinetic behavior

at relatively high plasma cocaine concentrations. A major concern is

depression of left ventricular function, which is probably the result of the local

anesthetic actions of cocaine. Depression of left ventricular function induced by

cocaine has been described in isolated hearts (Abel et al. 1989) as well as in

anesthetized dogs (Hale et al. 1989). More recently, severe, translent

depression of left ventricular function has been demonstrated in conscious dogs

that received cocaine, 4 mg/kg IV (Fraker et al. 1990).

Although most studies involving human volunteers report peak plasma cocaine

concentrations of less than 1 mg/L, plasma cocaine concentrations determined

at autopsy of individuals who died shortly after cocaine use have been much

higher. In one recent study, the average cocaine plasma concentration found at

autopsy was 6.2 mg/L with a range of 0.1 mg/L to 17 mg/L (Wetli and Wright

1979). Thus, abnormalities in cardiac electrophysiology as well as convulsions

37
also may result from the local anesthetic actions of cocaine. Any or all these

effects associated with extremely high cocaine plasma concentrations may lead

to severe morbidity or mortality.

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Fraker, T.D.; Temesy-Armos, P.N.; Brewster, P.S.; and Wilkerson, R.D.

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ACKNOWLEDGMENT

This work was supported by National lnstitute on Drug Abuse (NIDA) grant DA04038 and NIDA contract 271-87-8130.

AUTHORS

R. Douglas Wilkerson, Ph.D.

Professor of Pharmacology

Department of Pharmacology

Peter N. Temesy-Armos, M.D.

Associate Professor of Medicine

Theodore D. Fraker, Jr., M.D.

Associate Professor of Medicine

Division of Cardiology

Department of Medicine

The Medical College of Ohio

P.O. Box 10008

Toledo, OH 43899

40
Acute Tolerance to the Chronotropic

Effect of Cocaine in Humans

John J. Ambre, Timothy J. Connelly, Tsuen-lh Rue,

and Thomas K. Henthorn

INTRODUCTION

Acute tolerance develops to the cardiac chronotropic and subjective effects of

cocaine in humans (Chow et al. 1985). In previous studies Ambre and

colleagues (1988) showed that tolerance to the chronotroplc effect is

incomplete; that is, heart rate decline in the presence of stable plasma cocaine

concentrations approaches a plateau that is still higher than the baseline heart

rate. They also found that tolerance development can be described as an

exponential process with a half-time averaging 28 minutes and that by

producing steady-state cocaine concentrations, the extent of tolerance

development also can be determined (Ambre et al. 1988). The studies

described here aim at full specification of a pharmawkinetic and dynamic model

by determining the rate of tolerance loss (return of cocaine responsiveness). A

quantitative description of tolerance may help us understand patterns of drug

use and provide a basis for developing testable hypotheses about the

mechanisms involved in the tolerance process.

METHODS

Acute tolerance to cocaine was induced by two procedures: long- and shortterm cocaine exposures. Loading doses followed by steady-state cocaine

infusions (long-term exposure) were used, as in our previous studies, to induce

a full or maximal state of tolerance. The Identical injectlon or loading dose

producing similar peak plasma levels, but with no further infusion (short-term

exposure), was given in separate study sessions. Cocaine challenge injections

then were given at various Intervals after tolerance induction to determine the

rate of tolerance loss.

41
Dosage Regimens

Subjects received an intravenous (IV) dose of approximately 100 mg cocaine

delivered by a constant-rate syringe pump over 10 minutes (loading dose)

followed by an infusion designed to maintain stable plasma concentrations in

the range of 1,000 ng/mL. Cocaine infusions were continued for 3 hours to

allow full tolerance development (long-term exposure). in other sessions, an

identical loading dose was given without the infusion (short-term). A 50 or 100

mg challenge dose was administered over 10 minutes in each subject at an

interval of 2, 4, and/or 20 hours from the end of the induction dose, depending

on the study. Placebo studies consisted of saline infusion.

Investigational Drug

Vials containing a sterile, nonpyrogenic, 10 mg/mL (33.0 μmol/L as the base)

solution of cocaine hydrochloride (HCI) in water was prepared In the Pharmacy

Department of Northwestern Memorial Hospital (cocaine HCI USP-flakes,

Mallinckrodt Inc., St. Louis, MO). The required infusion solutions were prepared

from this solution under sterile conditions by the hospital pharmacy IV admixture

service. A portion of each dose solution used in each study was taken for

quantitative analysis as described below to verify calculation of the administered

dose and demonstrate stability of the dose solution. (Dr. Ambre holds an

Investigational New Drug application from the Food and Drug Administration for

the cocaine HCI preparation used in these studies.)

Subjects

The subjects were healthy adult male volunteers, 32 to 42 years of age, with a

history of IV cocaine use at least once a week for 2 years. Prior cocaine use

was determined (Chow et al. 1985; Ambre et al. 1988) to ensure that subjects

were experienced, confirmed cocaine users. Each had used a variety of other

drugs in the past but was using only alcohol and/or marijuana around the time

of the study. Subject characteristics are shown in table 1. Each subject was

informed of the nature of the study and its potential hazards and signed a

written consent form that had been approved by the Institutional Review Board

of Northwestern University. Subjects underwent a medical history evaluation, a

complete physical and psychiatric examination, chest x-ray, electrocardiogram

(ECG), 25-test blood chemistry panel, urine drug screen, and serum

cholinesterase determination, The subjects were clinically well nourished and

weighed within 10 percent of ideal weight as estimated for their height and build

(Hamwi 1964).

42
TABLE 1. Subject characteristics

Subject

Age

(yr) Sex

Height Weight

(cm) (kg)

20 32 M 183 77

21 32 M 173 73

22 35 M 165 61

23 42 M 175 77

24 40 M 177 75

25 37 M 183 90

26 41 M 178 84

27 25 M 175 76

28 42 M 175 77

29 27 M 182 86

30 34 M 167 65

Conduct of Study

Subjects were asked to abstain from cocaine use for at least 2 days before the

study. On the night before the study they were admitted to the Clinical

Research Center at Northwestern University Medical School. Urine was taken

for drug screening to detect recent drug use, including thin-layer

chromatography by the commercially available TOXI-LAB system (Analytical

Systems, Laguna Hills, CA), and a battery of immunoassay tests for drugs of

abuse in urine (Abbott TDx tests for cocaine, amphetamines, opioids,

phencyciidine, cannabinoids, methaqualone, barbiturates, and benzodiazepines

(Abbott Laboratories, North Chicago, IL). The use of a single 15 to 30 mg (49.5

to 99.0 μmol) dose of cocaine can be detected by urine testing for at least 48

hours afterwards (Ambre 1985).

On the study day a heparin lock was placed in a forearm vein for blood

sampling, and an IV line was established in the other arm for drug

administration. The electrodes for a continuous ECG monitor and a blood

pressure cuff were put in place. Subjects were continuously monitored by the

physician investigators. The cardiovascular monitoring system is a Marquette

Series 7000 ECG Telemetry Unit (Marquette Electronics inc, Milwaukee, WI)

that provides real-time display at the bedside of a high-resolution ECG tracing,

six-beat average heart rate record, and ST segment position. Subjects were

sitting or semireclining in bed throughout the study. The urinary bladder was

emptied, and the urine was analyzed again for drugs of abuse. After these

43
preparations baseline measurements were taken for at least 30 minutes while

the subject was undisturbed.

Laboratory Methods

Blood samples were drawn into Vacutainer tubes (Becton-Dickinson,

Rutherford, NJ) containing sodium fluoride and potassium oxalate (Chow et al.

1985; Ambre et al. 1988). Plasma was separated immediately and stored at

-20°C until analyzed. Plasma cocaine concentrations were determined by gas

chromatography/mass spectrometry on a Hewlett-Packard MSD system as

described previously (Chow et al. 1985). The method has a detection limit of

approximately 5 ng/mL (.016 μmol/L) using a 0.5 mL sample. Sample extracts

were injected twice. The coefficient of variation was less than 10 percent for

samples between 100 and 5,000 ng/mL (0.33 and 18.5 μmol/L).

Pharmacokinetic Analysis

Kinetic analyses were made with CONSAM 30, an interactive version of the

SAAM 27 modeling program (Berman and Weiss 1978) and implemented on a

VAX 11/785 computer (Digital Equipment Corporation, Boston, MA) and more

recently on an 80388 microcomputer. Curve fitting and data analysis were done

on data obtained from an individual subject. Cocaine disposition was

appropriately modeled with a one- or two-compartment open system with

elimination from the central compartment. Parameter values for this model

were adjusted iteratively by the computer program to optimize the fit of the

theoretic plasma level curve to the experimental data. The parameter estimates

of the disposition model then were used to fit the pharmacodynamic model to

the effect data in each subject by nonlinear least squares regression.

RESULTS AND DISCUSSION

Figures 1 and 2 show plasma cocaine levels and chronotropic response in a

cocaine infusion experiment. Plasma levels rise during the 10-minute loading

injection and then are maintained relatively constant during the infusion. Heart

rate reaches a peak at the end of the 10-minute injection, declines toward a

plateau, and finally declines with concentrations when the infusion is stopped.

The data were evaluated as plots of effect vs. concentration at each plasma

sampling point in temporal sequence (phase plots). On an idealized effect-vsconcentration plot, when no distributional lag, tolerance, or other phenomenon

distorts the relationship, intensity of effects follow drug concentrations, and

rising and falling limbs of the phase plot are superimposed. Acute tolerance

development is associated with clockwise opening (hysteresis) of the phase

loop.

44
FIGURE 1. Plasma cocaine concentrations during an infusion of “long-term,

cocaine exposure” experiment. Cocaine concentrations rise

during the 10-minute constant rate injection and then remain

relatively constant during the infusion.

Figures 3 and 4 show typical phase plots for tolerance-inducing infusions in

individual subjects. Heart rate rises sharply during the injection and then begins

to fall even as concentrations continue to rise slightly to the appropriate steady

state. The vertical segment of the loop represents the infusion period when

concentrations are stable but heart rate is falling due to tolerance development.

Full tolerance development is indicated by clustering at one coordinate. When

the infusion is stopped, heart rate declines with concentration. Data from an

early 4-hour challenge dose show that tolerance is still maximal. The plot

shows the characteristics of a phase plot without the distortion produced by

varying degrees of increasing tolerance. The slope of the initial response is

decreased and the limbs of the phase plot are nearly superimposed on each

other as well as the declining limb of the induction plot. Response also is

shown to be linearly related to concentration in the presence of tolerance (up to

1,200 ng/ml). Data from challenge doses at 20 hours indicate that tolerance

has been lost (or sensitivity restored). Phase plots show initial slopes identical

to the original response, and some clockwise opening of the loop may be

45
FIGURE 2. Heart rate (beats per minute) in response to the cocaine

infusion described in figure 1. Heart rate reaches a peak at the

end of the injection dose and then declines toward a plateau

despite the constant level of cocaine. Heart rate then declines

with the decline in cocaine concentration when the infusion is

stopped.

evident. Phase plots from all subjects show the identical characteristics. A

challenge dose administered when sensitivity is partially restored gives the

expected Intermediate result. Results show that maximal tolerance persists at 4

hours after the induction infusion and that tolerance disappears at 20 hours.

The studies at challenge intervals between 4 and 20 hours are still in progress;

these results will be required to fully define the rate of tolerance loss. Existing

results, however, allow some conclusions about the design of a

pharmacodynamic model. In earlier studies we used a model that mainly

allowed data description and calculation of the tolerance development rate

without mechanistic assumptions. Other investigators have proposed tolerance

models. A model used for nicotine but proposed to be generally applicable to

other abused drugs is the “antagonist-force” model of Porchet and coworkers

(1988). This model postulates the generation of a hypothetical substance (or

48
FIGURE 3. Phase plots of data obtained during a tolerance-inducing (3

hours long) infusion and challenge injections at 4 hours and 20

hours after the end of the infusion. As described in the text, the

position and contour of the 4-hour plot indicate that tolerance is

still present. Data from the 20-hour challenge dose indicate that

tolerance has been lost (or sensitivity restored).

alternatively a “force”) that acts as a noncompetitive antagonist of the

chronotropic effects of nicotine. Generation of the antagonist is driven by

nicotine concentrations in the central kinetic compartment. A limitation of the

model is the requirement that the rates of development and disappearance of

tolerance be identical. With a half-time for cocaine acute tolerance

development of about 30 minutes, the Porchet model would predict return of full

sensitivity within 3 hours (five or six half-lives). Our results show that this

clearly is not the case for cocaine, under conditions of our study, simulating

typical exposure. Figure 5 shows heart rate data from one subject that were

fitted to the Porchet model and then plotted with the model-predicted response

to a 4-hour challenge dose.

47
FIGURE 4. Phase plots of data obtained during a tolerance-inducing infusion

and challenge injection at 4 hours after the end of the infusion in

subject 24. As described in the text, the position of the 4-hour

challenge dose plot indicates the continued presence of

tolerance.

Porchet and colleagues applied their model to data collected during short

infusions of nicotine. Data for our short-term cocaine exposure studies are

shown in figures 6 and 7. In these studies, 100 mg of cocaine was given by

constant injection pump over 10 minutes without further infusion of cocaine.

Challenge doses of cocaine (50 to 100 mg) were given over 10 minutes at

intervals of 2 and 4 hours. Phase plots of the results (figures 6 and 7) show

that tolerance present at 2 hours was reversed at 4 hours. These results

suggest that the duration or intensity of cocaine exposure influences the rate of

tolerance reversal. Although the rate of tolerance onset is similar after singleinjection (short-term) or steady-state infusion (long-term induction) (Ambre et al.

1988), after prolonged exposure the time constant for regression is longer than

that for tolerance development.

48
FIGURE 5. Data from a study involving cocaine injection/infusion followed by

a 4-hour challenge dose were fitted to the model of Porchet and

colleagues. The closed circles are measured heart rate data, and

the solid line indicates model-predicted response. The model

clearly predicts the return of initial sensitivity at 4 hours, whereas

the actual response is blunted, indicating persistent tolerance.

Although the Porchet model may be applicable for short-term exposure, it

clearly is not adequate to describe our infusion data. The kinetic behavior and

magnitude of the tolerance factors for the cardiac chronotropic effect of cocaine

suggest a relation to rate constants for events in adrenergic receptor systems

(Porchet et al. 1988). According to a common concept of adrenergic receptor

systems (Levitzki 1988), agonists interact with beta-adrenergic receptors;

adenylate cyclase is activated; and cyclic adenosine monophosphate is

produced within the cell. If agonist exposure continues, cellular response

decreases (desensitization) as a result of component processes with different

time courses: (1) Receptors are uncoupled from adenylate cyclase and/or

redistributed from the cell surface (internalized); this process has a short time

course and is reversible. (2) The number of (detectable) receptors decreases;

this process has a longer time course and is less readily reversible.

40
FIGURE 6. Phase plots of a study in subject 29 involving short-term exposure

to cocaine (100 mg of cocaine by constant injection pump over 10

minutes) and a challenge dose 2 hours later. The slope and

position of the challenge dose plot indicate the presence of

tolerance.

Our results indicate that tolerance induced by short-term (single injection)

cocaine exposure is more rapidly reversible than that induced by more

prolonged (cocaine infusion) exposure. Based on the above concept, these

results suggest that the apparent tolerance is related to receptor alteration and

that rapidly reversible processes (e.g., receptor uncoupling and/or

internalization) may predominate in tolerance induced by short-term cocaine

exposure, and more slowly reversible processes (e.g., receptor catabolism) may

become significant when cocaine exposure is prolonged.

We propose a model of acute tolerance that is based on receptor pharmacology

(figure 8) and incorporates rapidly reversible and more slowly reversible

processes. Such a model should allow description of cocaine response and

tolerance regardless of exposure conditions. In this model, the receptor is

synthesized (process 1) and activated but is also subject to inactivation and/or

unavailability (reversible process 3) and can be degraded or catabolized

(process 2). Computer simulations, using the CONSAM 30 program, of brief

50
FIGURE 7. Phase plots of a study in subject 29 involving short-term, exposure

to cocaine (100 mg of cocaine by constant infusion pump over 10

minutes) and a challenge dose 4 hours later. The two plots are

superimposed, indicating identical responsiveness or loss of

tolerance.

(figure 9) and prolonged (figure 10) exposure to cocaine and subsequent

challenge, show their effects on the population of active receptors. Studies of

the two exposure conditions, both in terms of in vivo responsiveness to beta

agonists and in vitro receptor status, should allow characterization of the rates

of the component processes of the model. Current studies are aiming at

verification of this model.

51
FIGURE 8. Proposed model of a receptor system subject to tolerance

induction. In this model, receptor is synthesized (process 1) and

then activated but is a/so subject to inactivation and/or

unavailability (reversible process 3). The inactive receptor can be

degraded or cataboiized (process 2).

FIGURE 9. Computer simulation of the response of the heart rate and

proposed receptor system to brief exposure to cocaine and

subsequent cocaine challenge. The population of responsive

receptors declines with exposure and returns to baseline levels

quickly.

52
FIGURE 10. Computer simulation of the response of heart rate and the

proposed receptor system to prolonged exposure to cocaine and

subsequent cocaine challenge. Responsive receptors decline

during exposure and return slowly to baseline levels.

REFERENCES

Ambre, J.J. The urinary excretion of cocaine and metaboiites in humans: A

kinetic analysis of published data. J Anal Toxicol 9:241-245, 1985.

Ambre, J.J.; Belknap, S.M.; Nelson, J.; Ruo, T-l.; Shin, S-G.; and Atkinson, A.J.,

Jr. Acute tolerance to cocaine in humans. Clin Pharmacol Ther 44:1-6,

1988.

Berman, M., and Weiss, M.F. SAAM Manual. DHEW Pub. No. (NIH)78-180.

Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1978.

Chow, M.J.; Ambre, J.J.; Ruo, T-l.; Atkinson, A.J., Jr.; Bowsher, D.J.; and

Fischman, M. Kinetics of cocaine distribution, elimination, and chronotropic

effects, Clin Pharmacol Ther 38:316-324, 1985.

Hamwi, G.J. Therapy: Changing dietary concepts. In: Danowski, T.S., ed.

Diabetes Mellitus: Diagnosis and Treatment. Vol 1. New York: American

Diabetes Association, 1964. pp. 73-78.

Levitzki, A. From epinephrine to cyclic AMP. Science 241:800-806, 1988.

Porchet, H.C.; Benowitz, N.L.; and Sheiner, L.B. Pharmacodynamic model of

tolerance: Application to nicotine. J Pharmacol Exp Ther 244:231-236,

1988.

53
ACKKNOWLEDGMENTS

This chapter was prepared with support from National Institute on Drug Abuse

grant DA-04073 and General Clinical Research Center Branch, Divislon of

Research Resources, National Institutes of Health, grant RR-00048. The

SAAM/CONSAM computer programs were provided by the USPHS/NIH/DRRNHLBI-NCI joint development project.

AUTHORS

John J. Ambre, M.D., Ph.D.

Director

Department of Toxicology

American Medical Association

515 North State Street

Chicago, IL 60610

Timothy J. Connelly, M.D.

Resident

Department of Anesthesiology

University of Wisconsin Hospital

800 Highland Avenue

Madison, WI 53792

Tsuen-lh Ruo, Ph.D.

Associate Professor of Medicine

Clinical Pharmacology Center

Department of Medicine

Thomas K. Henthorn, M.D.

Assistant Professor

Department of Anesthesia

Northwestern University Medical School

303 East Chicago Avenue

Chicago, IL 60611

54
Mechanisms of Cardiac and Vascular

Responses to Cocaine

Mark M. Knuepfer, Carrie A. Branch, and Vernon W. Fischer

INTRODUCTION

Cocaine is a potent central nervous system (CNS) stimulant and local

anesthetic with limited clinical usefulness that has become one of the most

widely abused drugs in the United States. Cocaine’s high abuse potential is

due to its ability to produce euphoria within minutes and central arousal for up to

an hour in humans (Fischman et al. 1976; Fischman 1984; Van Dyke et al.

1979). Behavioral models of addictive and hedonistic potential and selfstimulation studies have demonstrated that cocaine also is a powerful

reinforcing agent in nonhuman animals (Johanson and Balster 1978; Kornetsky

et al. 1979; Wise 1984). in addition to its euphoric effects, cocaine produces

cardiovascular responses usually described as modest pressor response and

tachycardia in conscious animals and humans. Although the mechanisms

eliciting these cardiovascular responses are as yet unclear, the responses

presumably are due to direct potentiation of catecholaminergic activity and

indirect (CNS-mediated) sympathoexcltation. Within the past decade, there has

been a dramatic increase in the number of clinical reports associating cardiac

abnormalities and cocaine use. Life-threatening and sometimes fatal cardiac

toxicity by unknown mechanisms reportedly has occurred after inhalation or

infusion of cocaine in otherwise asymptomatic patients. Our studies have

attempted to identify the mechanisms whereby cocaine produces its vascular

and cardiac effects in conscious animals, with particular interest in studying

cardiotoxic reactions and elucidating appropriate therapeutic interventions for

these responses.

EFFECTS OF COCAINE ON HEMODYNAMICS

Several studies on the effects of cocaine have examined the physiological

effects on arterial pressure (AP) and heart rate (HR) and the behavioral effects

in conscious animals; related studies also have been performed in humans

(Fischman et al. 1976; Fischman 1984; Van Dyke et al. 1979; Chow et al. 1985;

Resnick et al. 1977). Studies in anesthetized animals have examined in detail

55
the effects on adrenergic systems (Gunne and Jonsson 1964; Hadfield et al.

1980; Masuda and Levy 1984; Tariuo and Rubio 1985); however, recent

studies show that anesthesia alters cardiovascular responses to cocaine

(Wilkerson 1988; Knuepfer et al. 1987). Little is known concerning the effects of

cocaine on the heart and vasculature in conscious animals.

Several observations have been made while examining cocaine’s actions on

cells and tissues. Cocaine is a competitive antagonist for neuronal uptake of

catecholamines via the energy-dependent, uptake I pump (Gilman et al. 1985;

Wise 1984); it also binds to other cellular sites (Kuhar et al. 1988; Reith 1988).

Studies performed in vitro have demonstrated that cocaine causes increases in

norepinephrine release and contractility of smooth muscle in response to

electrical stimulation (Langer and Enero 1974) or to exogenous

sympathomimetics (Kalsner and Nickerson 1969). Chronotropic and lnotropic

responses to sympathetic nerve stimulation were potentiated by cocaine in

isolated heart muscle (McCulloch et al. 1974) but not in intact, anesthetized

animals (Masuda and Levy 1984; lnoue and Zipes 1988). However, recently,

Gillis and coworkers (this volume) observed potentiated responses to

sympathetic nerve stimulation when low doses of cocaine were injected into

anesthetized cats. Exogenous sympathomimetics elicit positive chronotropic

and inotropic effects on the myocardium and a pressor response that is

potentiated by cocaine in anesthetized dogs (Levy and Blattberg 1978; lnoue

and Zipes 1988). Cocaine caused a decrease In the positive chronotropic effect

of norepinephrine in excised atria that was interpreted to be due to a rapidly

induced, lowered sensitivity of beta-adrenergic receptors to sympathomimetics

(Tarizzo and Rubio 1985). Data describing the cardiovascular effects of

cocaine in conscious animals are limited almost entirely to analyses of AP and

HR responses. Our studies have examined regional vascular and cardiac

responses to cocaine to describe more completely the mechanisms by which

cocaine produces its complex effects and to determine how drugs antagonize

specific responses to cocaine.

The regional vascular effects of acute cocaine administration were examined in

unanesthetized, freely moving rats, which were surgically prepared using sterile

technique 3 to 5 days in advance. Rats were Instrumented for measurement of

AP, HR, and regional vascular blood flows. Miniaturized pulsed Doppler flow

probes were implanted on the abdominal aorta and the superior mesenteric

artery for estimates of hindquarters (skeletal muscle) and mesenteric (visceral)

blood flows, as described by Haywood and coworkers (1981).

Before drug administration, mean AP was 111 +/-3 mmHg and HR was 470+/-1 3

beats/min (n=19). Responses to cocaine (0.25-10 mg/kg IV[intravenous]) were

variable, but dose-related increases in AP and mesenteric vascular resistance

56
and decreases in HR and, occasionally, vascular resistance in hindquarters

were observed (data not shown). Administration of 5 mg/kg cocaine produced

changes as shown in figure 1. The AP response is characterized by an acute

pressor response lasting less than 1 minute, hereafter referred to as the peak

response, followed by a sustained modest pressor response. Although the data

confirm these peak responses, as described in previous studies, they are short

Iived. These data also demonstrate that cocaine does not produce a

generalized vasoconstrlctor response, but it does elicit a response

characterized by visceral vasoconstrictlon and, in some cases, skeletal muscle

vasodilation. Occasionally, there was a modest, Initial increase in HR occurring

within the first 30 seconds after cocaine administration that preceded a

profound, long-lasting bradycardia. These responses were reproducible when

rats were given cocaine twice daily for up to 2 weeks. Behaviorally, rats

appeared aroused and often had an apparent increase in locomotor activity,

repetitive head movements, and, in a few cases at high doses, tonic-clonic

seizure activity. Data from rats demonstrating seizure activity were not included

In these analyses.

MECHANISMS MEDIATING CARDIOVASCULAR EFFECTS OF COCAINE

These studies examined several mechanisms by which cocaine may produce

its cardiovascular effects. Because cocaine has a local anesthetic action that

may contribute to its cardiovascular effects, the cardiovascular effects of

procaine were compared with those of cocaine in conscious rats (figure 2). Due

to the difference in magnitude or direction of the peak and sustained responses,

these were analyzed independently using a paired Student’s t-test and a twoway, split-plot, two-way analysis of variance, respectively. Procaine (10 mg/kg)

produced a significantly smaller peak pressor response (PEAK) and a

somewhat smaller sustained pressor response than that of cocaine (figure 2,

panel A). The reduced pressor response apparently was dependent on a

significantly smaller mesenteric vascoconstrictor response. A tachycardiac

response after procaine, instead of a bradycardiac response, contributed to the

pressor response. Equivalent doses of procaine have been reported to partially

mimic the cardiovascular effects of cocaine in rats (Pitts et al. 1987). Because

cocaine is at least twice as potent in blocking neuronal conduction (Skou 1954),

it is likely that the higher dose of procaine more aptly mimics the local

anesthetic effects of cocaine. These results suggest that cocaine’s vascular

effects are not likely to be mediated by its local anesthetic actions.

Because it generally is thought that CNS-mediated sympathoexcitation and

baroreflex-mediated vagal activity contribute to the responses elicited by

cocaine (Gilman et al. 1985; Wilkerson 1988), the roles of the sympathetic and

parasympathetic nervous systems were investigated. Ganglionic blockade

57
FIGURE 1. Effects of cocaine (5 mg/kg IV) on arterial pressure (AP in mmHg)

and heart rate (HR in beats/min) in panel A and on hindquarters

and mesenteric vascular resistance (HqR and MesR,

respectively) in panel B. Changes and percent changes are

shown at the time of the PEAK and at 1, 3, and 5 minutes after

cocaine administration. Note the large magnitude of the peak

responses in comparison to the modest, sustained responses.

58
FIGURE 2. A comparison of the effects of cocaine (5 mg/kg IV) with those of

procaine (10 mg/kg IV). The differences in each response

(denoted as in figure 1) were obtained by subtracting changes

elicited by procaine from those elicited by cocaine at different

periods after drug administration. Responses were analyzed

using a split-plot, two-way analysis of variance. Peak responses

also were analyzed independently using Student’s t-test.

Significant differences (p<0.05) are denoted by an asterisk for

analysis of variance and a star for Student’s t-test.

59
using pentolinium (7.5 mg/kg) elicited falls in AP, HR, and regional vascular

resistances (table 1). Subsequent cocaine administration (5 mg/kg IV)

demonstrated an attenuated PEAK with no effect on the sustained pressor

response (figure 3, panel A). The reduced PEAK was coincident with a

reduction in mesenteric vasoconstriction (figure 3, panel B). Therefore, the

early initial pressor response may be due to a CNS-mediated sympathoexcitation, but the sustained responses (after 30 seconds) appear to be

mediated primarily by peripheral actions of cocaine. These data are consistent

with those of Wilkerson (1988), who reported an attenuation of the PEAK after

ganglionic blockade in conscious dogs, although it is not clear from this report

whether the sustained modest pressor response also was attenuated in dogs.

The bradycardiac response to cocaine was blocked by pentolinium without

affecting the regional vascular responses (figure 3, panel A). Similarly,

peripheral muscarinic receptor blockade with methylatropine (0.5-1 mg/kg)

resulted In an Increase in HR. Subsequent administration of cocaine (5 mg/kg

IV) revealed a significant decrease in the bradycardiac response (data not

shown). These results suggest that the bradycardiac response is dependent on

an increase in vagal tone, presumably due to activation of the baroreceptors.

TABLE 1. Effects of receptor antagonists on cardiovascular parameters

Arterial pressure

(mmHg)

Heart rate

(beats/min)

Hindquarter resistance

(percent change)

Mesenteric resistance

(percent change)

Pentolinium Propranolol

-36±2* 3±1

-83±11* -65±8*

-28±6* 6±3

-17±4* 8±3*

*Significantly different from control (p<0.05) using paired Student’s t-test

Although nonspecific beta-adrenergic receptor antagonists, such as

propranolol, have been proposed by one group of investigators to be effective in

the treatment of cocaine-induced cardiotoxic responses (Rappolt et al. 1977,

1979; Gay 1982) few data are available suggesting that such effects are

pharmacologically indicated. The effects of propranoiol on hemodynamic

responses to cocaine were examined. Propranolol (1 mg/kg) alone produced a

significant decrease in HR and a slight increase in mesenteric vascular

60
FIGURE 3. The effects of ganglionlc blockade with pentolinium (7.5 mg/kg IV)

on responses to cocaine (5 mg/kg IV are depicted. Pentolinium

was administered 10 minutes before cocaine and compared with

responses obtained with cocaine alone. The changes in

responses caused by gang/ionic blockade are shown and

analyzed as described in figure 2.

61
resistance without affecting other parameters (table 1). Pressor responses to

cocaine were exacerbated due to a reversal of the vascular response In

hindquarters from a vasodiiation to a vasoconstrlction (figure 4). Interestingly,

selective beta,-adrenergic receptor blockade with metoprolol had no effect on

responses to cocaine (data not shown). Therefore, beta2-adrenergic receptors

appear to have a beneficial effect on cocaine intoxication, at least with respect

to attenuating the pressor responses and, presumably, the increase in

myocardial oxygen demand. This observation may raise concerns with regard

to the rationale for using propranolol clinically in cocaine-related cardiotoxicity.

Reports have shown that propranolol does not protect dogs or monkeys from

the lethal effects of cocaine (Catravas and Waters 1981; Guinn et al. 1980), and

at least two clinical reports also have suggested that propranolol may be

detrimental due to unopposed alpha-adrenergic-mediated vasoconstriction

(Ramoska and Sacchetti 1985; Olson et al. 1983).

CARDIOTOXIC EFFECTS OF COCAINE-FUNCTIONAL STUDIES

There are a growing number of clinical reports relating cocaine use to the

occurrence of serious and sometimes fatal ischemic heart disease (Isner et al.

1986; Kossowsky and Lyon 1984; Mathias 1986; Pasterneck et al. 1985;

Schachne et al. 1984; Simpson and Edwards 1986; Tazelaar et al. 1987; Wetli

and Wright 1979: Zimmerman et al. 1987). Typically, patients had symptoms of

angina pectoris or ventricular fibrillation within an hour after intranasal or IV

cocaine administration, and electrocardiograms and/or serum creatine

phosphokinase levels indicated substantial to severe myocardiai infarction. In 6

of 14 patients who underwent angiography, normal coronary arteries were

observed. Many patients had coronary obstructive disease, usually without any

other signs of atherosclerosis or occlusive disease and with minimal risk factors,

Three hypotheses have been used to describe the transient myocardial

ischemia observed after cocaine use: (1) local occlusive spasm of a major

coronary artery with resultant transmural ischemia leading to infarction

(Kossowsky and Lyon 1984; Pasternack et al. 1985; Schachne et al. 1984;

Zimmerman et al. 1987); (2) induction of platelet aggregation by alphaadrenergic stimulation leading to thrombotic occlusion of a coronary artery

(Isner et al. 1986; Simpson and Edwards 1986); and/or (3) extreme elevations

in HR and AP resulting in subendocardial ischemia due to excessive myocardial

oxygen demand (Pasterneck et al. 1985). Our studies were undertaken in a rat

model to elucidate the mechanisms by which cocaine induces cardiomyopathies

as the data from these studies might provide an insight for potential therapeutic

intervention and to examine the rationale for the commonly prescribed

treatment of cocaine-related cardiotoxlcity with propranolol (Rappolt et al. 1977;

Rappolt et al. 1979; Gay 1982).

62
FIGURE 4. The effects of beta-adrenergic receptor blockade with propranolol

(1 mg/kg IV on responses to cocaine (5 mg/kg IV) are depicted

as described in figure 3 and analyzed as described in figure 2.

63
FIGURE 5. Effects of cocaine (5 mg/kg IV on AP, HR, and CO at times after

cocaine administration described in figure 1. Note the minimal

effect of cocaine on CO.

Using functional and anatomical techniques, the effects of cocaine on the

myocardium in conscious, freely moving rats were examined. Rats were

instrumented for AP and HR determination and for continuous measurement of

ascending aortic blood flow as a measure of cardiac output (CO) using

miniaturized pulsed Doppler flow probes as described by Werber and coworkers

(1984). Estimates of total peripheral resistance and stroke volume also were

made using these variables. After 5 to 7 days for recovery, rats were treated

with cocaine (0.5-5 mg/kg IV) for analysis of the cardiac and vascular

components of cocaine’s action in conscious, freely moving rats. Cocaine

elicited increases in total peripheral resistance with little effect on stroke volume

(figure 5). Therefore, the data suggest that cocaine-induced cardiomyopathies

in rats are not dependent on a sustained increase in afterload or direct cardiac

stimulation but may be dependent on local ischemia resulting from vasospasm

or thrombotic occlusion. These studies supported the observations described

earlier with beta-adrenerglc antagonists, suggesting that cocaine’s stimulatory

effects on the heart may be minimal. Indeed, recent observations in humans

also have suggested that propranolol may exacerbate cocaine-related cardiac

abnormalities (Ramoska and Sacchetti 1985; Olson et al. 1983).

64
During the analysis of these data, it became apparent that changes In CO

elicited by cocaine were not similar in all rats. In approximately two-thirds of the

rats, cocaine produced little or no change in CO, whereas in one-third of the

animals, a profound, acute drop in cardiac output of varying magnitude (20 to

80 percent) was observed (figure 6). These functional deficits in myocardial

FIGURE 6. An example of responses to cocaine (5 mg/kg IV) in a rat that

apparently experienced a cardiotoxic response. The AP and HR

responses did not appear different than responses observed in

other rats (see mean responses in figures 1 and 5) yet were

severely compromised. This response followed pretreatment with

propranolol (1 mg/kg) but also was observed without any

pretreatment. The time scale, shown at bottom, includes a period

showing phasic blood flow in the ascending aorta without

electronic filtering.

65
activity were observed either relatively consistently in Individual rats or not at all,

despite the total number of trials with cocaine. Acute impairment of cardiac

function was observed In rats with normal pressor and bradycardiac responses

to cocaine, indicating that earlier studies measuring only AP and HR probably

missed identifying this higher sensitivity. Again, propranoloi pretreatment did

not prevent this cardiotoxic response in “responding” rats; yet, prazosin

appeared to prevent the toxicity (data not shown). Furthermore, significant

elevations in CO did not precede the profound fall, further supporting the

findings described herein that cocaine does not elicit cardiac stimulation either

directly or indirectly.

CARDIOTOXIC EFFECTS OF COCAINE-ANATOMICAL STUDIES

Two studies have reported the presence of contraction bands in myocardiai

tissue on postmortem analyses in cocaine users, a cardinal sign of myocardiai

dysfunction (Simpson and Edwards 1986; Tazelaar et al. 1987). These

observations are described further in this volume by Drs. Billingham and

Virmani. Recently, the appearance of myocardial contraction bands has been

considered as an anatomical basis for arrhythmias associated with cocaine

administration (Karch and Billingham 1988). It also has been suggested that

their presence, although not conclusive, may provide evidence for the cause of

death in cases of cocaine abuse without other demonstrable abnormalities

(Simpson and Edwards 1986; Tazelaar et al. 1987).

Limited experiments have been performed that attempt to correlate functional

deficits in the myocardlum elicited by cocaine administration with structural

alterations of myocardiai tissue. At the completion of experiments measuring

cardiac function, 14 rats were sacrificed, and their hearts were removed rapidly.

One-millimeter cubes of ventricular myocardiai tissue were placed immediately

in 3 percent giutaraidehyde in Sorensen’s phosphate buffer at pH 7.2, postfixed

with osmium tetroxide (1 percent at pH 7.2), and processed routinely for viewing

in a JEOL 100 CX electron microscope. For light microscopic orientation,

plastic embedded sections, 1 μm thick, were stained with alkaline methylene

blue. The remainder of the heart was fixed In 10 percent neutral, buffered

formalin and was dehydrated, embedded in paraffin, and examined by light

microscopy. Myocardiai tissues from similarly instrumented rats that did not

receive cocaine were examined in a similar manner. The myocardiai tissues

were examined by an investigator who was unaware of the functional data

obtained (double blind).

Examination of the myocardiai tissues revealed specific alterations that

appeared to be related to the functional sensitivity to cocaine as well as

changes that were present in all rats regardless of their exposure and

66
responsiveness to cocaine. Figure 7 is an electron micrograph of cardiac tissue

from the rat whose cardiovascular responses to cocaine are shown in figure 6.

Figure 8 is a micrograph from another rat with a similar cardiotoxic reaction to

cocaine. These micrographs demonstrate a marked translucency of

mitochondrial matrices with disruption of the cristae, hypercontraction of

myofibrils, and subsarcolemmal and intramyocytic dilations of the sarcoplasmic

reticulum. Minimal, highly focal changes were seen in myocardiai tissue of

control and “nonresponding” rats. These included large numbers of pinocytotic

vesicles within endothelial ceils, patches of interstitial fibrosis, and widening of

intermyocytic spaces. Although these changes may be a consequence of the

surgical and experimental interventions, they appeared to be exacerbated in

“responding” rats. Interestingly, specific alterations in the myocardium using the

protocol were not identifiable at the light microscopic level with the exception of

an epicarditis, which most likely resulted from damage and irritation of this

tissue associated with the operative procedures and foci of fibrosis. Although

additional detailed studies of the correlation between functional and anatomical

changes induced by cocaine are necessary to verify these observations, the

changes observed in these preliminary studies suggest that cocaine may cause

substantial cardiac damage in a subset of the population, even with limited

exposure.

CONCLUSIONS

Our data demonstrate that, in the majority of rats, cocaine produces a dosedependent, short-lasting pressor response, followed by a modest pressor

response dependent on an increase in total peripheral resistance with little

effect on stroke volume or CO. The increase in peripheral resistance was due

in part to mesenteric vasoconstrictlon and counteracted in part by a modest

vasodiiation in the vascular bed of the hindquarters. The vasoconstrictor

responses were due to alpha,-adrenergic receptor activation, whereas the

vasodiiator responses appeared to be due to activation of beta2

-adrenergic

receptors. The authors suggest that these responses are mediated indirectly by

cocaine’s ability to potentiate the effects of catechoiamines in plasma and at the

neuroeffector junction. We found no evidence for a central component of

cocaine’s vasoconstrictor effects. Approximately one-third of the rats appeared

to have moderately to severely acute decrements in CO after cocaine

administration. This higher sensitivity to cocaine’s functional cardiotoxic effects

was mirrored in more severe alterations in myocardiai cells, including an

apparently greater incidence of contraction bands, mitochondriai and

myofibrillar disruption, and foci of fibrosis in “sensitive” rats. The functional

deficits In the myocardiai responses could not be prevented with propranoloi,

but they may be attenuated by prazosin.

67
FIGURE 7. An electron micrograph from the myocardium of a rat after

cocaine administration (physiologic data shown in figure 6). Note

the hypercon tracted, electron-dense myocardiocyte (top half of

picture) in contrast to the electron-lucent cell in the lower half.

The latter cell shows widely dilated sarcoplasmic reticular profiles

and foci of interfibrillar and intrafibrillar lucency. In addition, a few

mitochondria exhibit loss of matrical density. Original

magnification x 12,500.

68
FIGURE 8. An electron micrograph demonstrating changes in

myocardiocytes from another rat with a cardiotoxic response to

cocaine. Note focal electron-lucency within myocyte in the center

of the picture with derangement and loss of contractile elements,

In addition, the pericapillary space is filled with fluid resembling

that present within the capillary lumen. A profusion of transcytotic

vesicles also can be seen in the capillary endothelium. Original

magnification x 5,000.

69
Many studies have described the local anesthetic actions, the potentiation of

central and peripheral monoamine action, and the behavioral stimulation elicited

by cocaine. The studies described here and in this volume present the first

comprehensive description of the effects of cocaine on the cardiovascular

system. These observations are important in understanding the mechanisms of

cocaine’s actions and In treating deleterious effects of cocaine in humans.

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ACKNOWLEDGMENTS

David M. Wehner provided assistance in preparing instrumented rats and

performing experiments. This work was supported in part by U.S. Public Health

Service grants HL-38299 from the National Heart, Lung, and Blood Institute and

DA-05180 from the National Institute on Drug Abuse.

AUTHORS

Mark M. Knuepfer, Ph.D.

Associate Professor of Pharmacology

Department of Pharmacological and Physiological Science

Carrie A. Branch, B.S.

Department of Pathology

Vernon W. Fischer, Ph.D.

Professor of Anatomy

Departments of Anatomy and Neurobiology and Pathology

St. Louis University School of Medicine

1402 South Grand Boulevard

St. Louis, MO 63104

73
Cardiovascular Effects of Cocaine in

Squirrel Monkeys

Sriharl R. Tella, Charles W. Schindler, and Steven R. Goldberg

INTRODUCTION

The latest National Institute on Drug Abuse surveys indicate that toxic

consequences of cocaine abuse are on the rise. Although occasional use of

cocaine may be down, long-term use and Its consequences are up, as Indicated

by hospital emergency room admissions. However, the precise mechanism of

cocaine toxicity is not well understood.

Cocaine is a central nervous system (CNS) stimulant with local anesthetic and

sympathomimetic properties. The serious toxic manifestations reported appear

to be of central and cardiovascular origin. Recent clinical reports show the

potential of cocaine to cause cardiovascular complications such as angina and

acute myocardial ischemia resulting in infarction, cardiac arrhythmias,

myocarditis, and dilated cardiomyopathy (Duke 1986; Mathlas 1986; Frishman

et al. 1989). Among the cocaine-associated cardiovascular complications,

acute myocardial infarction can lead to sudden death due to cardiac pump

failure or accompanying cardiac arrhythmias. The pharmacological basis of

cocaine-related myocardial infarction is uncertain. Various possibilities Include

coronary artery spasm, thrombosis, or an increased workload on the

myocardium due to the pressor and tachycardiac effects of cocaine (Frishman

et al. 1989). In subjects with underlying coronary artery disease, the

simultaneous increase in blood pressure (BP) and heart rate (HR) can evoke

myocardial ischemla via an increase in myocardial oxygen demand. Persistent

increases in BP and HR also can lead to other serious clinical conditions such

as pulmonary and cerebral edema and hemorrhage. Therefore, understanding

the nature and mechanism of the pressor and tachycardiac effects of cocaine is

clinically Important.

Cocaine is thought to produce Its excitatory effects on the cardiovascular

system by inhibiting the neuronal reuptake of norepinephrine at sympathetic

nerve terminals (MacMillan 1959; Whitby et al. 1960; Muscholl 1961; Matsuda

et al. 1980). However, there Is an efficient negative feedback mechanism

74
regulating synaptic or junctional levels of norepinephrine within the physiological

range (Langer 1981; Starke 1987) that makes it difficult to implicate this

property of cocaine in its prolonged cardiovascular effects. Furthermore, other

uptake inhibitors such as desipramine do not produce cardiovascular responses

comparable to those produced by cocaine (Wilkerson 1978). These findings

suggest that, in addition to the inhibition of neuronal reuptake of norepinephrlne,

other mechanisms also might be operative in eliciting the prolonged pressor and

tachycardiac effects of cocaine. Possible mechanisms include central nervous

stimulation leading to an increase in peripheral sympathetic tone (Wilkerson

1988) and/or direct action of cocaine on sympathetic nerve terminals causing

the release of norepinephrine (Campos et al. 1963; Maengwyn-Davies and

Koppanyi 1966; Trendelenburg 1968; Tessel et al. 1978; Palaty 1988).

Most earlier studies have examined the cardiovascular effects of cocaine In

anesthetized animals, ignoring the possible mediation of its intense central

actions. To examine the importance of some of the above-mentioned

mechanisms, this chapter reviews the cardiovascular effects of cocaine in intact

conscious squirrel monkeys and in monkeys under halothane or pentobarbital

anesthesia.

GENERAL METHODS

The monkeys were surgically prepared with chronic catheters In the abdominal

aorta and in the right atrium. Catheters were implanted under halothane

anesthesia via the right internal iliac artery and vein and were used for

recording BP and for intravenous (IV) injection of drugs. The free ends of the

catheters were passed under the skin to the monkey’s back where they exited

the skin. Catheters were filled with heparinized saline (20 units/mL) and closed

with stainless steel obturators. Animals wore nylon mesh jackets to protect the

catheters. A postoperative recovery period of 2 to 3 weeks was allowed before

any experimentation.

During experimental sessions, chronically catheterized monkeys were seated in

Plexiglas chairs within illuminated, sound-attenuating chambers 5 days a week

for a period of 90 minutes per day. Pressure signals from the arterial catheter

were processed via a pressure transducer, an amplifier, and a BP processor

(Coulbourn Instruments, Allentown, PA). The output from the BP processor

was analyzed online by an Apple IIe computer for recording systolic, diastolic,

and mean arterial BP and HR. The computer averaged the above parameters

over a period of 30 seconds. A lead II electrocardiogram was recorded on a

chart recorder using needle electrodes to monitor cardiac rhythm and to further

verify HR changes. Cocaine hydrochloride (0.01-3.0 mg/kg) was administered

as an IV bolus injection over a period of 15 seconds on Tuesdays and Fridays,

75
and saline was administered on Thursdays. Only one dose of cocaine was

tested on each day of drug intervention. Cocaine or saline was administered 30

minutes after the start of the experimental session. Parts of these results have

been reported elsewhere (Tella et al. 1990).

EFFECTS OF COCAINE ALONE

Cocaine alone produced a dose-dependent increase in BP that was linear over

the dose range tested (figure 1). At 3.0 mg/kg, cocaine produced approximately

a 30-percent increase in BP. Cocaine’s effects on HR were not as clearly dose

dependent. Figure 1 shows a linear increase in HR up to 0.3 mg/kg; above this

dose HR plateaued, which may be due to a tendency for the higher doses of

cocaine to produce decreases in HR immediately after administration. Figure 2

compares the effects of 0.3 and 3.0 mg/kg injections of cocaine on HR as a

function of time since injection. At the 0.3 mg/kg dose of cocaine, HR was

increased by approximately 26 percent, with the peak effect occurring

approximately 20 to 30 minutes following the injection. At the higher dose of

3.0 mg/kg, however, the peak increase in HR was delayed. At this dose there

was also an initial bradycardia followed by tachycardia approximately 15 to 20

minutes following the injection of cocaine, and the peak tachycardiac effect

occurred 50 minutes following the injection.

EFFECTS OF ANESTHESIA AND GANGLIONIC BLOCKADE

Table 1 presents the baseline BP and HR values for the various experimental

conditions. Pentobarbital, halothane, and hexamethonium treatments all

reduced BP, whereas pentobarbttal and halothane reduced HR. When

monkeys were anesthetized wlth either pentobarbitai (25 mg/kg IV) or halothane

(1.75 percent), the pressor (p<0.05 to 0.01) and tachycardiac (p<0.01)

responses to cocaine were reduced markedly (table 2). Antagonism of the

pressor response to cocaine by halothane was significantly greater (p<0.01)

than that by pentobarbital. Haiothane, but not pentobarbitai, significantly

reduced (p<0.01) the pressor response to exogenously administered

norepinephrine (data not shown). The IV administration of 15 mg/kg

hexamethonium, 10 minutes before an IV dose of 3 mg/kg cocaine, together

with a slow intra-arterial infusion of hexamethonium (0.1 mg/kg/min) throughout

the session, failed to antagonize the pressor or tachycardiac effects of cocaine

(figure 3). As cocaine-induced cardiovascular responses were not abolished by

hexamethonium pretreatment in conscious animals and were reduced

differently by the two anesthetic agents, the primary mechanism involved in

cocaine’s actions may not be the activation of the CNS-sympathoadrenai neural

axis but the drug’s peripheral effects on neuronal release and function.

76
FIGURE 1. Effects of cocaine on peak changes in BP (mmHg) and HR (beats

per min) in six conscious squirrel monkeys. Error bars are +1 SE.

Baseline BP was 113.2+7.9 mmHg, and baseline heart rate was

266+6 bears per minute.

SOURCE: Tella et al. 1990, copyright 1990, American Society for

Pharmacology and Experimental Therapeutics.

77
FIGURE 2. Time course for the effects of two doses of cocaine (0.3 and 3.0

mg/kg) on HR for those subjects presented in figure 1 (n=6).

Note the delayed occurrence of tachycardia to 3 mg/kg cocaine

as opposed to 0.3 mg/kg cocaine. Note also the initial

bradycardia with the 3 mg/kg dose.

SOURCE: Tella et al. 1990, copyright 1990, American Society for

Pharmacology and Experimental Therapeutics.

These results do not agree with an earlier study demonstrating the predominant

role of a centrally mediated increase in sympathoadrenal discharge in the

cardiovascular effects of cocaine in conscious dogs (Wilkerson 1988). There

appear to be several other qualitative and quantitative differences in the

cardiovascular effects of cocaine in conscious dogs and squirrel monkeys.

First, the HR response to cocaine, unlike BP, reached the plateau of the logdose response curve at 0.3 mg/kg dose In squirrel monkeys; in dogs the HR

and BP responses continued to increase up to the highest dose of 8 mg/kg

tested. Second, the peak pressor responses observed with cocaine in dogs are

much larger than those in squirrel monkeys (Tella et al. 1990). For example, a

dose of 0.3 mg/kg cocaine produced a 21-percent increase in BP in squirrel

78
TABLE 1. Effects of pharmacological pretreatments on baseline BP and HR

Drug BP (mmHg) HR (Beats/Min)

Control Postdrug Control Postdrug

Control 113.2 + 7.9 266.0 + 0.0

Pentobarbital 104.3+ 10 73.2 + 13.3* 263.8 + 7.9 167.2 + 10.1*

Halothane 104.3+ 10 65.3 + 5.8* 263.8 + 7.9 220.4 + 24.8*

Hexamethonium 110.4 + 10.5 95.2 + 10.3* 203.8 + 7.9 266.2 + 19.8

Phentolamine 104.3+ 10 56.8 + 5.8* 258.5 + 6.9 301.3 + 16.3*

Propranolol 104.3 + 10 111.3 + 4.4 258.5 + 6.9 195.2 + 13.1*

NOTE: Each value is the mean of 4 to 5 subjects.

*p<.05.

SOURCE: Tella et al. 1990, copyright 1990, Williams and Wilkins.

TABLE 2. Effects of anesthesia on the cardiovascular effects of 3.0 mg/kg

cocaine injections

Peak Change After Cocaine

Blood Pressure (mmHg)

Heart Rate (beats/min)

Conscious Halothane

39.0+ 5.3 9.3+2.4

70.4+19.0 18.2 + 6.9

Pentobarbitai

28.7+5.7

12.6 + 4.6

NOTE: N=4 to 5 per cell. For baseline values, see table 1.

SOURCE: Tella et al. 1990, copyright 1990, Williams and Wilkins.

monkeys, which is comparable to the 15- to 20-percent increase seen in human

subjects (Resnick et al. 1977; Fischman and Schuster 1982). In contrast, a

comparable dose of cocaine produced approximately a 40-percent increase in

BP in conscious dogs, and increases as large as 70 to 100 percent were

produced by 4 to 8 mg/kg doses of cocaine, Third, there are differences in the

duration of cardiovascular effects of cocaine in monkeys and dogs. The BP and

HR response to a 3 mg/kg dose of cocaine lasted more than 1 hour in squirrel

monkeys (Tella et al. 1990), whereas in dogs these responses lasted for a

maximum of 20 minutes with the highest dose tested of 8 mg/kg (Wilkerson

1988).

79
FIGURE 3. Effects of hexamethonium (n=5), phentolamine (n=4), or

propranolol (n=4) on the peak pressor (mmHg) and tachycardiac

(beats/min) effects of a 3 mg/kg IV dose of cocaine in conscious

squirrel monkeys. Cocaine was administered at 30 minutes after

the start of the experimental session. Hexamethonium was

administered as an initial IV loading dose of 75 mg/kg given 10

minutes before the administration of cocaine, followed by a slow

intra-arterial infusion at a rate of 0.1 mg/kg/min throughout the

experimental period of 90 minutes. Phentolamine was administered

as an initial IV loading dose of 3 mg/kg 5 minutes before the start of

the session followed by a slow intra-arterial infusion of 30 μg/kg/min

throughout the session. Propranolol was administered as a 3 mg/kg

IV dose 5 minutes before the start of the experimental session.

Control (n=5) represents the effects of cocaine obtained in normal

conscious monkeys on a different day. Data are expressed as

mean + 1 SE. See table 2 for baseline values.

SOURCE: Tella et al. 1990, copyright 1990, American Society for

Pharmacology and Experimental Therapeutics.

80
These differences in duration are probably of pharmacodynamlc rather than

pharmacokinetic origin, as the plasma half-lives of cocaine in dogs (72 min) and

monkeys (72-78 min) are comparable (Misra 1976). Differences in the actions

of cocaine in dogs and squirrel monkeys do not appear to be due to different

doses or routes of administration because these also were comparable. Also,

the mean baseline BP of conscious monkeys averaged about 110 mmHg,

which was comparable to 109 mmHg reported In conscious dogs. The doses of

cocaine employed in both series of experiments were within the range of the

steeper portion of their corresponding log-dose pressure-response curves. The

doses of hexamethonium employed In the present work were sufficient to

completely antagonize the reflex reduction in HR caused by norepinephrlne

(1 mg/kg IV), thus indicating the presence of an adequate blockade of

autonomic ganglia.

Other evidence favoring the mediation of the CNS-sympathoadrenal neural axis

in the cardiovascular effects of cocaine includes the fact that cocaine causes

the release of catecholamines at least in part via this pathway in conscious rats

(Chiueh and Kopin 1978). However, these catechoiamine levels were

measured 15 minutes after the administration of cocaine; the cardiovascular

effects of cocaine in this species have a mean duration of about 15 seconds

(Pitts et al. 1987). The above data indicate possible species differences In the

mechanisms of cocaine’s cardiovascular effects. increases In activity of the

CNS-sympathoadrenal neural axis do not seem to be the primary mechanism in

the pressor and tachycardiac actions of cocaine in conscious squirrel monkeys.

Failure to antagonize the cardiovascular effects of cocaine by prior blockade of

autonomic ganglia suggests that these effects are not due to potentiation of

tonically released norepinephrine from sympathetic nerve terminals.

Presynaptic inhibitory mechanisms theoretically would tend to counteract any

increase in synaptic norepinephrine levels resulting from cocaine-induced

inhibition of neuronal uptake mechanisms. Thus, the inhibition of neuronal

uptake of norepinephrine by cocaine does not explain completely the prolonged

cardiovascular effects of cocaine.

EFFECTS OF ADRENERGIC BLOCKADE

We also have studied the effects of alpha and beta adrenoceptor blockade on

the cardiovascular effects of cocaine. Pretreatment with phentolamine

prevented the pressor effect of cocaine, whereas propranolol blocked the

cocaine-induced increase in HR (figure 3). The decrease in the magnitude of

the cocaine-induced HR increase by phentoiamine may be due to the dramatic

increase in baseline HR produced by phentolamine (table 1). These results

suggest that the cardiovascular effects of cocaine in squirrel monkeys are

81
mediated primarily by the peripheral adrenergic nervous system. The results,

however, do not rule out another possible mechanism of centrally mediated

cardiovascular effects of cocaine; that is, cocaine may act centrally to cause the

release of some pituitary hormones that subsequently act peripherally on the

sympathoadrenal system (Gothert 1981) to elicit, or at least contribute to, the

sustained excitatory cardiovascular effects.

The source of catecholamines mediating cocaine’s pressor and tachycardiac

effects in conscious squirrel monkeys remains in question. It is possible that

cocaine may have a direct effect on the adrenal medulla causing release of

catecholamines. However, recent in vitro evidence obtained from adrenal

medullary chromaffin cell culture studies has shown that cocaine has no direct

effects on catecholamine release but, on the contrary, inhibits the release of

catecholamines evoked by nicotine, veratroldine, and ouabain, but not

potassium (Powis et al. 1989). It Is also possible that cocaine causes release of

norepinephrine from sympathetic nerve terminals, similar to indirectly acting

sympathomimetic agents, and subsequently inhibits neuronal reuptake of the

released noreplnephrine. Experimental evidence obtained from intact animals

and in vitro organ preparations suggests that cocaine, like indirect

sympathomimetic agents, releases norepinephrine from sympathetic nerve

terminals (Campos et al. 1963; Maengwyn-Davies and Koppanyi 1966;

Trendelenburg 1968; Tessel et al. 1978; Palaty 1988). It has been shown that

depletion of norepinephrine stores from peripheral sympathetic nerve terminals

by repeated injection of ephedrine blocks the pressor effects of cocaine in

spinal cats. This suggests the importance of peripheral sites of norepinephrine

release (Teeters et al. 1963).

INDIVIDUAL EFFECTS

in squirrel monkeys higher doses of cocaine tended to produce an initlal

bradycardia, followed by increases in HR 20 to 60 minutes following the

injection. However, this tendency to produce bradycardia is not evident in all

monkeys. Although all the monkeys showed a delayed tachycardiac response

to cocaine, the tachycardia was not always preceded by bradycardia. These

intriguing, individual differences in HR effects of cocaine led to a search for an

explanation.

For the six monkeys whose results are presented in figures 1 and 2, the 1 and 3

mg/kg bolus doses of cocaine caused an initial bradycardia ranging from 10 to

30 beats/minute in three monkeys and a large reduction of 90 and 110 beats/

minute in one of six monkeys tested in this study. None of the pharmacological

interventions discussed above prevented the moderate bradycardia caused by

cocaine in three monkeys. However, when cocaine was administered as a slow

82
infusion over a 10-minute period, no bradycardia occurred. Thus, this moderate

bradycardia produced by cocaine may be due to cocaine’s direct depressant

effect on the pacemaker function of the heart (Trendelenburg 1968; Tessel et

al. 1978). Contrary to this, the large bradycardia caused by cocaine in one

monkey was not prevented by slow infusion but was completely blocked by

hexamethonium (15 mg/kg IV+0.1 mg/kg/min slow intra-arterial infusion) and

was attenuated by atropine (1 mg/kg intramuscular) or propranolol (1 mg/kg IV).

The pronounced bradycardia produced by cocaine in this one monkey may

have been due to a baroreceptor reflex response secondary to cocaine’s

pressor effects. Pharmacological interventions that reduced the pressor

response to cocaine, such as the use of general anesthesia and phentolamine

treatment, prevented this large bradycardia (figure 4).

Figure 5 shows a further analysis of the time course for the 3.0 mg/kg dose of

cocaine. The subjects for this analysis were broken down according to

subspecies. The Guyanan subspecies of squirrel monkeys showed clear

bradycardia following cocaine, whereas “other” monkeys, which were primarily

Peruvian, did not (p<.001). Figure 5 also shows the study results of Gonzalez

and Byrd (1977) who reported that cocaine produced only tachycardia in

squirrel monkeys; their results are clearly comparable to our results for the

“other” monkeys. These results clearly indicate that even subtle genetic

differences may produce large differences in the effects of cocaine and that

these differences may account for much of the variability observed following

cocaine. An appreciation of these potential genetic differences in cocaine’s

effects has gained considerable recognition lately (George and Goldberg 1989;

ishizuka et al. 1989).

Although our recent studies never have noted cocaine-produced arrhythmias,

cocaine could potentiate a preexisting arrhythmia. For example, one subject

showed a low level of ectopic beats following saline injections. As shown in

figure 8, a cocaine dose of 3.0 mg/kg potentiated that arrhythmia. Following

saline in this monkey, ectopic beats rarely occurred at a rate exceeding 10 per

minute. Following cocaine, however, an average of more than 20 beats/minute

was observed. The large standard error following cocaine suggests some

caution in the interpretation of these results; nevertheless, it does suggest the

possibility that cocaine may influence the electrical rhythm of the heart if an

abnormal rhythm preexists.

TOLERANCE

It has been reported that in human subjects acute tolerance develops to the

effects of successive doses of cocaine on HR (Fischman et al. 1985; Foltin et

al. 1988) but not on BP (Foltin et al. 1988). However, in these studies the BP

83
FIGURE 4. Effects of various pharmacological interventions on the peak

bradycardiac effect of a 3 mg/kg IV bolus injection of cocaine in

one monkey (S1086). Note the partial antagonism of the

bradycardia by atropine and propranolol. These drugs were

administered 5 minutes before the start of the experimental

session. Pentobarbltal anesthesia, phentolamine treatment, or

hexamethonium interventions completely prevented the

bradycardiac effect of cocaine. Time and mode of administration

of these three drugs were the same as those described in figure

3.

SOURCE: Tella et at. 1990, copyright 1990, American Society for

Pharmacology and Experimental Therapeutics.

and HR increases caused by the first dose of cocaine had not subsided

completely before administration of the second dose. it remains to be

determined whether tolerance still occurs if the doses of cocaine are spaced at

intervals allowing responses to the first dose of cocaine to completely subside

before administration of a second dose. in this study with squirrel monkeys, the

84
FIGURE 5. Time course for the effects of 3.0 mg/kg cocaine in various groups

of monkeys. Monkeys were divided into two groups according to

subspecies (Guyanan n=4, all “others” n=3). Also plotted are the

results from Gonzalez and Byrd (1977) for 3.0 mg/kg cocaine.

BPM=beats/min; MM=mmHg.

85
FIGURE 8. Frequency of ectopic beats following IV injection of 3.0 mg/kg

cocaine or saline for one monkey (S-1-87). The cocaine curve

represents the mean of four sessions. The saline curve is a

single representative session. Error bars are + 1 SE.

HR response to cocaine reached a maximum at the 0.3 mg/kg dose. In

contrast, the BP response to cocaine continued to rise with increasing doses up

to the highest dose tested (3.0 mg/kg). The possible occurrence of such a

plateau phase to the HR response to cocaine also should be considered when

evaluating the possible development of tolerance to the HR effects of cocaine in

humans. Due to ethical reasons a systematic human dose response study

using higher doses of cocaine could not be conducted. However, careful

examination of the data of Fischman and colleagues (1976) indicates that such

a plateau phase to HR response, as seen in squirrel monkeys, might occur in

humans. It also has been reported that acute tolerance to the HR effects of

cocaine occurs in rhesus monkeys (Matsuzaki et al. 1976). Administration of

cocaine (2-4 mg/kg IV) at 24-hour intervals resulted in reduced HR and

respiratory rate responses to cocaine, suggesting development of acute

tolerance lasting at least 24 hours. These data should be viewed with some

86
FIGURE 7. Changes in HR (beats/min) and BP (mmHg) following IV

administration of a 0.3 mg/kg dose of cocaine on 5 consecutive

days in three monkeys. Monkeys were allowed to remain drug

free for 10 days before the start of this protocol. Cocaine was

administered once per day for 5 consecutive days.

8 7
caution as HR is a particularly complex parameter to measure because it is

susceptible to changes due to baroreceptor reflex control secondary to the

pressor effects of cocaine. Unfortunately, BP was not measured in the study by

Matsuzaki and coworkers. In contrast, our experiments with squirrel monkeys

failed to show such tolerance to either the pressor or the tachycardiac effects of

a 0.3 mg/kg IV dose of cocaine administered at 24-hour intervals for 5

consecutive days (figure 7). Development of tolerance to the cardiovascular

effects of cocaine needs further exploration using a wider range of doses.

CONCLUSIONS

Cocaine elicits pressor and tachycardiac effects in conscious squirrel monkeys,

and in some monkeys higher doses of cocaine also cause an initial bradycardia

before tachycardia. The mechanism of cocaine’s cardiovascular effects

appears to be complex in nature. Stimulation of the CNS-sympathoadrenal

neural axis, unlike in dogs, does not appear to be the main pathway in eliciting

the pressor and tachycardlac effects of cocaine in conscious squirrel monkeys.

Possible mechanisms include peripheral effects on the sympathoadrenal

system and/or central neuroendocrine effects of cocaine. Higher doses of

cocaine appear to elicit bradycardia by a direct depressant action on the

pacemaker function of the heart or by baroreceptor reflex in response to

cocaine’s pressor effects. In addition, study data show that certain animals are

more sensitive to cocaine’s cardiotoxlc effects than others. No clear tolerance

development to the effects of repeated cocaine administration was observed.

However, because limited doses were studied, this area of investigation

requires further analysis.

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cocaine on catecholamine levels in subcellular fractions of the Isolated cat

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Chiueh, C.C., and Kopin, I.J. Centrally mediated release by cocaine of

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Fischman, M.W.; Schuster, C.R.; Resnekov, L.; Shick, J.F.E.; Krasnegor, N.A.,

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Gonzalez, F.A., and Byrd, L.D. Physiological effects of cocaine in the squirrel

monkey. Life Sci 21:1417-1424,1977.

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of indirectly acting sympathomimetic drugs In the rabbit aortic strip and In

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Mathias, D.W. Cocaine-associated myocardial ischemia: Review of clinical and

angiographic findings. Am J Med 61:675-678, 1986.

Matsuda, Y.; Masuda, Y.; Blattberg, B.; and Levy, M.N. The effects of cocaine,

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Pitts, D.K.; Udom, C.E.; and Marwah, J. Cardiovascular effects of cocaine in

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autonomic neural mechanisms in the cardiovascular effects of cocaine in

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HCI and a quaternary derivative of cocaine, cocaine methiodide, on isolated

guinea-pig and rat atria. J Pharmacol Exp Ther 205:569-576, 1978.

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noradrenaline labelled with tritium. Nature 187:604-605, 1960.

Wilkerson, R.D. Antiarrhythmic effects of tricyclic antidepressant drugs In

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674, 1976.

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J Pharmacol Exp Ther 246:466-471, 1988.

AUTHORS

Srihari R. Tella, Ph.D.

Research Assistant Professor

Georgetown University

3900 Reservoir Road, N.W.

Washington, DC 20007

Charles W. Schindler, Ph.D.

Research Psychologist

90
Steven R. Goldberg, Ph.D.

Chief

Preclinical Pharmacology Branch

Behavioral Pharmacology and Genetics Laboratory

Addiction Research Center

National Institute on Drug Abuse

P.O. Box 5180

Baltimore, MD 21224

91
Role of the Sympathetic Nervous

System in the Cardiovascular

Effects of Cocaine

Richard A. Gillis, Lisa C. Bachenheimer, Kenneth L. Dretchen,

Hashim K. Erzouki, Yvonne M. Hernandez, Rakesh K. Jain,

Muskesh K. Jain, Fred E. Kuhn, Jack Quest, and Gary L. Schaer

INTRODUCTION

Many of the cardiovascular effects of cocaine have been attributed to

sympathomimetic actions of the drug. The peripheral nervous system and the

brain have been studied as potential sites for the sympathomimetic actions of

cocaine. In terms of the peripheral nervous system, one of cocaine’s important

actions is to block the uptake of catecholamines such as norepinephrine into

sympathetic postganglionic nerve terminals, thereby allowing higher

concentrations of norepinephrine to interact with the physiological postsynaptic

receptor site. In terms of the central nervous system (CNS), it has been

proposed that cocaine increases sympathetic nerve activity and that the site of

this action is in the brain (Chiueh and Kopin 1978; Wilkerson 1988). Our study

had three purposes: The first was to determine whether cocaine potentiates

sympathetic neural effects on the heart. Interestingly, previous data from

experiments in which cocaine was tested on cardiac responses elicited by

cardiac sympathetic nerve stimulation generally indicate an inability of cocaine

to potentiate the responses to cardiac sympathetic nerve stimulation (Pappas et

al. 1965; Johnson and Kahn 1966; Koerker and Moran 1971; Levy and

Blattberg 1976, 1978; Matsuda et al. 1980; lnoue and Zipes 1988). The second

was to determine whether cocaine increases central sympathetic outflow. In

this regard, a careful review of published papers on cocaine fails to provide

direct evidence that cocaine stimulates sympathetic centers. The third was to

determine whether any observed changes in sympathetic nervous system

activity produced by cocaine contribute to the cardiovascular effects elicited by

the drug.

92
METHODS

Experiments were performed on adult cats and dogs of both sexes. Cats were

anesthetized either with intravenous (IV) alpha-chloralose, 70 to 80 mg/kg (for

the majority of the experiments), or pentobarbital sodium, 35 mg/kg IV (for the

experiments in which sympathetic neural activity was recorded). Dogs were

anesthetized with thiopental sodium (25 μg/kg IV) followed by intubation with a

cuffed endotracheal tube. Sufentanil was given as an IV bolus (2 μg/kg)

followed by a continuous IV infusion (1 mg/kg/hr) to achieve a constant level of

sedation throughout the experiment. Pancuronium bromide (0.1 mg/kg IV) was

given as needed to provide continuous skeletal muscle relaxation. In the cat

experiments, the trachea was cannulated, and the animals were allowed to

breathe spontaneously, except in the sympathetic nerve recording studies in

which the cats were artificially ventilated with room air. A femoral artery and

vein were routinely cannulated for measurement of arterial blood pressure and

systemic administration of drugs, respectively. Rectal temperature was

monitored and maintained between 37°C and 38°C by an infrared lamp. For

the sympathetic nerve recording experiments, vecuronium bromide was

administered (initial IV bolus of 0.02 mg/kg followed by a continuous infusion of

0.15 mg/kg/hr) to produce skeletal muscle paralysis: respirator settings were

adjusted to maintain end-tidal CO, between 4.0 and 5.0 percent (CO, monitor

[IL 200]).

In the dog studies, the following indices of cardiovascular function were

measured and/or derived: heart rate by Lead II of the electrocardiogram (ECG),

arterial blood pressure (catheter in the aortic root), transmural myocardial blood

flow (colored microsphere technique, Hale et al. 1988) coronary vascular

resistance (derived by dividing mean arterial pressure by myocardial blood

flow), left anterior descending epicardial coronary vessel diameter (coronary

angiography), and cardiac output (thermodilution technique). Details of the

techniques are described by Kuhn and colleagues (1990).

In the cat studies, measurements were made of heart rate (standard limb leads

of the ECG plus augmented leads and a chest lead for analysis of sinus rate,

ST segment changes, conduction changes, and cardiac rhythm changes) and

arterial blood pressure (catheter in the femoral artery).

In cat studies in which the postganglionic cardioaccelerator nerve was

electrically stimulated, the animals were subjected to bilateral cervical vagotomy

and to spinal cord transection at the atlanto-occipital junction to eliminate all

cardiovascular reflexes.

93
The technique for electrical stimulation of the postganglionic cardioaccelerator

nerve was the same as that described by Aiken and Reit (1968). To gain

access to this nerve, the right chest was opened in the first intercostal space.

The stellate ganglion and its neural connections were exposed by bluntly

dissecting away the surrounding fat and connective tissue. The

cardioaccelerator nerve was dissected free and placed on bipolar stimulating

electrodes. The sympathetic trunk containing preganglionic fibers synapsing at

the stellate ganglion was exposed and cut.

Electrical stimulation of the cardioaccelerator nerves was applied with a

conventional stimulator (Grass). Supramaximal square-wave impulses of 0.5

msec in duration were used. The frequency of stimulation was set in each

experiment to elicit a heart rate response that was about 40 percent of the

maximal response attainable. This increase was approximately 30 to 35 beats/

min and was elicited with a frequency of stimulation ranging between 0.5 and 3

Hz. Each train of stimulation was applied for 30 to 45 seconds, a duration long

enough to give a steady-state effect. The basis for selecting a 40-percent

maximal response and the corresponding low frequency of stimulation is that

cocaine has been demonstrated to potentiate submaximal responses but not

maximal responses elicited by sympathetic nerve stimulation (Trendelenburg

1959). Atropine methylbromide, 0.5 mg/kg IV, was administered routinely to

each animal to eliminate effects that might arise from activation of any

cholinergic fibers, which have been described as coursing with the

cardioaccelerator nerve (Juhasz-Nagy and Szentivanyi 1961).

The following experimental protocol was used: (1) Supramaximal voltage was

determined by increasing voltage while maintaining constant impulse duration

(0.5 msec) and frequency of stimulation (usually 1 to 3 Hz). Supramaximal

voltage was set at a value approximately 5 V in excess of the voltage required

to produce a maximal increase in heart rate. (2) Maximal heart rate obtainable

in each animal was determined by increasing the frequency of stimulation (up to

20 to 25 Hz). (3) The frequency of stimulation then was adjusted to produce a

heart rate increase that was about 40 percent of the maximal increase

attainable. (4) Electrical stimulation was performed at 6-minute intervals. (5)

Once three to four reproducible responses to sympathetic nerve stimulation

were obtained, cocaine was administered and sympathetic nerve stimulation

was repeated. In some experiments, norepinephrine was administered

intravenously. The dose chosen was one that would produce approximately the

same increase in heart rate as sympathetic nerve stimulation (i.e., in the range

of 0.7 to 1.5 μg/kg). Again, three reproducible responses were obtained using a

6-minute interval between dosing before testing the effect of IV cocaine. In all

cases, a value was calculated that indicated the degree of potentiation

94
produced by cocaine. This value is designated as magnitude of potentiation

and is calculated as follows:

Magnitude of Potentiation (%) =

additional heart rate

increase observed above

control response after cocaine x 100

heart rate increase

observed during the control period

For the purpose of injecting drugs into the vertebral artery of cats, retrograde

cannulation of the right axillary artery was performed. The tip of the cannula

was positioned at the bifurcation of this vessel with the vertebral artery after

ligating costocervical, thyrocervical, and internal mammary arteries (Van

Zwieten 1975). During periods of intra-arterial drug administration, the vertebral

artery was clamped between the bifurcation and the heart. The clamp was

removed after injection of a bolus of drug, thus allowing the flow of blood to

deliver the drug to the hindbrain. Cocaine was administered in a total volume of

0.1 mL followed by a saline flush of 0.3 mL, which represented cannula dead

space.

For the purpose of recording cardiac sympathetic nerve activity In anesthetized

cats, the right stellate ganglion was exposed by excising the first three ribs on the

right side from the sternum to the midaxillary line. The postganglionic

sympathetic cardiac nerve emerging from the stellate ganglion was dissected

free, sectioned distally, and desheathed. The nerve then was placed on bipolar

platinum-iridium recording electrodes and covered with mineral oil. Sympathetic

nerve discharges were amplified using a differential amplifier (Tektronix) with lowand high-frequency filters set at 10 and 3,000 Hz, respectively. The amplified

signal was displayed on an oscilloscope and recorded on magnetic tape.

Sympathetic nerve activity was quantified using a technique similar to that

employed by Eldridge (1971). The amplified pulses were halfway rectified and

fed into a voltage-frequency converter (Sample/Hold Integrator; BAK, Inc.), the

output pulse frequency of which is proportional to applied voltage. Integration

was accomplished by counting the voltage-to-frequency output pulses. The

output pulses were counted electronically in intervals of 10 msec. The digital

count, representing the electrical activity, was recorded on a recorder (Gould)

following digital-to-analog conversion. The data were analyzed directly from the

recorded tracing by averaging the amplitude of the peaks in the segment

immediately preceding drug administration and comparing this value to the

mean peak amplitude at the time of maximum drug response. Drug effects

were expressed as percent of control values.

95
The values stated in the text are mean±SEM. For most of the data calculations

in this study, statistical significance was determined by use of the Student’s

f-test for paired data and by use of Scheffe’s test when multiple comparisons

were made (Steel and Torrie 1980). The criterion for statistical significance was

p<=0.05.

RESULTS

The initial focus of the study was to examine cocaine for its ability to potentiate

the cardiac rate responses produced by electrical stimulation of postganglionlc

sympathetic nerves. A dose of 0.25 mg/kg was selected for study, because this

falls into the range of IV cocaine doses reported by Fischman and coworkers

(1985) to produce behavioral effects in humans that are similar to those

experienced when the drug is used on an illicit basis (i.e., doses of 18 to 49 mg,

equivalent to 0.23 to 0.89 mg/kg in a 70-kg subject). Figure 1 depicts the

results of a typical experiment in which a single dose of 0.25 mg/kg of IV

cocaine was tested for its effect on heart rate responses produced by electrical

stimulation of the cardiac accelerator nerves In an anesthetized cat.

Reproducible positive chronotropic control responses to nerve stimulation were

obtained at 0 and 6 minutes before cocaine administration. A bolus IV Injection

of 0.25 mg/kg of cocaine was administered; neural stimulation was repeated

within 1 minute after the IV injection was given. As can be noted, a marked

potentiation of the neurally evoked cardioaccelerator response was obtained

that was maximal at 1 minute after the injection.

A decline in the response was observed about 12 minutes after injection, and

the effect lasted for about 1 hour. Responses similar to this were observed in

each of 12 animals studied; the data are summarized in table 1 and indicate

that the magnitude of the potentiation of cardioaccelerator nerve stimulation by

0.25 mg/kg IV cocaine averaged 80 percent over control values. We were

unable to accurately evaluate the effect of cocaine on neurally evoked pressor

responses because of variations in the response during the control stimulation

periods and because the 30- to 40-second stimulation period was not long

enough to obtain a steady-state blood pressure response. The baseline values

for heart rate and mean arterial blood pressure in the animals studied were

143±9 beats/min and 47±2 mmHg, respectively. Cocaine administration alone

resulted in maximal changes in heart rate and mean arterial blood pressure of

+5±1.3 beats/min (p<0.05) and +11.2±4.3 mmHg (p<0.05) respectively.

We next studied the effect of repeated IV injections of 0.25 mg/kg of cocaine on

heart rate increases elicited by electrical stimulation of postganglionic cardiac

sympathetic nerves. The impetus for this was the clinical finding of Fischman

and coworkers (1985) that tachyphylaxis develops to the positive

96
FIGURE 1. Effect of cocaine on heart rate increases produced by electrical

stimulation of cardiac accelerator nerves in an anesthetized,

spinal cord transected cat. Control responses were obtained at 0

and 6 minutes before cocaine administration. Note the enhanced

response approximately 1 minute after cocaine (i.e., at 12

minutes) and restoration of the normal response at 66 minutes.

Columns depict the baseline levels (fiat end) immediately before

nerve stimulation; tips of arrows depict maximal increase in heart

rate during accelerator nerve stimulation.

SOURCE: Jain et al. 1990, copyright 1990, Williams and Wilkins.

97
TABLE 1. Effect of cocaine administration on heart rate increases induced by

electrical stimulation of postgangiionic cardiac sympathetic nerves

Additional HR

Increase Observed

HR Increase HR Increase Above Control Magnltude of

Dose of Number of Before Cocaine After Cocaine Response Potentiation

Cocaine Animals studied (beats/min) (beats/min) (beats/min) (percent)

0.25 mg/kg 12 31±2 55±2 24±2a80±10a

HR=Heart rate

using Student’s t-test for paired data

SOURCE: Jain et al. 1990, copyright 1990, Williams and Wilkins.

chronotropic effect of cocaine when human subjects were given IV doses of 16

to 40 mg of the drug 1 hour after using 94 mg of cocaine by the intranasal route.

Figure 2 shows a representative experiment in an anesthetized cat in which an

initial IV dose of 0.25 mg/kg of cocaine produced the expected enhancement in

the neurally evoked heart rate responses. That is, the heart rate increase

elicited by stimulation 1 minute after cocaine was 60 beats/min compared with a

36-beats/min increase before cocaine was given. When the tachycardiac

response to nerve stimulation returned to baseline level 2 hours later (plus 35

beats/min), a second IV dose of 0.25 mg/kg cocaine was given and was found

to produce a potentiating response of 50 beats/min that lasted 30 minutes. A

third dose of cocaine produced a potentiating response of only 45 beats/min,

suggesting the appearance of tachyphylaxis. The data obtained from five such

experiments are shown in table 2; the magnitude of potentiation of neurally

evoked tachycardia was 66±5, 19±6, and 24±4 percent after three successive

IV doses of cocaine.

The relationship between the amount of cocaine administered and the

magnitude of potentiation observed with nerve stimulation was examined by

testing IV doses of cocaine over the range of 0.0625 to 2.0 mg/kg. The results

are shown in table 3. Significant potentiation occurred with as little as 0.0625

mg/kg of cocaine, and linear dose-related increases in the magnitude of

potentiation were observed when the dose was doubled to 0.125 mg/kg and

again to 0.25 mg/kg. However, a significant dropoff in the magnitude of

potentiation occurred when larger doses of cocaine (0.5 mg/kg and 2.0 mg/kg)

were tested. An interesting point that emerged from these dose-response

studies was that tachyphylaxis did not occur to the potentiating effect of

the lowest dose of cocaine that was tested. An example of the

98
FIGURE 2. Effect of repeated injections of cocaine on heart rate increases produced by electrical stimulation of

cardiac accelerator nerves in an anesthetized, spinal wtd transected cat. Control responses were

obtained at 0 and 6 minutes before cocaine administration. Note the enhanced response approximately

1 minute afIer cocaine (i.e., at 12 minutes) and restoration of the normal response at 132 minutes. Note

the occurrenoe of tachyphyiaxis developing toward the enhancing effect of repeated doses of cocaine on

heart rate increases ewked by nerve stimulation. Columns depict baseline levels (flat end) immediately

before nerve stimulation, and tips of arrows depict maximal increase in heart rate during accelerator

nerve stimulation.
TABLE 2. Magnitude of potentiation of sympathetic nerve stimulation

response produced by cocaine on repeated dosing of 0.25 mg/kg

(n=5)

Dose

Number

HR Increase Before HR Increase

Cocaine (beats/min) After Cocaine

(control) (beats/min)

HR Increase

Observed Above

Control Response

Magnitude of

Potentiation

(percent)

1 39±1 57±1 23± a55±5a

2 39±1 47±2 8±2a,b 19±6a,b

3 37±2 45±2 8±1a,b 24+4a,b

HR=Heart rate

a

p<0.05 using Student’s t-test for paired data

b

p<0.06 when data are compared to data obtained with Dose No. 1 using Scheffe’s test

SOURCE: Jain et al. 1990, copyright 1990, Williams and Wilkins

tachyphylaxis development with the 0.0625 mg/kg dose is shown as figure 3.

As can be seen, before the first dose of cocaine, nerve stimulation increased

the heart rate by 35 beats/min. After the first dose of cocaine, this response

was increased to 46 beats/min. About an hour later nerve stimulation effects

were similar to the original response. The dose of cocaine was repeated and

produced a 54-beats/min increase in heart rate.

Additional studies were performed to evaluate the ability of cocaine (0.25 and

2.0 mg/kg IV) to potentiate the positive chronotropic effects of IV

norepinephrine. The doses of norepinephrine used in these studies ranged

from 0.25 to 1.4 μg/kg and were selected to produce chronotropic responses

similar to those obtained with nerve stimulation. The results obtained are

shown in table 3. With the 0.25 mg/kg cocaine dose, potentiation of

norepinephrine-induced increases in heart rate was observed, and the

magnitude of potentiation was similar to that observed with 0.25 mg/kg of

cocaine tested on neurally induced increases in heart rate. Interestingly, the

administration of 2.0 mg/kg of cocaine to animals resulted in a magnitude of

potentiation of norepinephrine-induced increase in heart rate that was

approximately four times greater than the magnitude of potentiation observed

when 2.0 mg/kg of cocaine was tested on neurally induced increases in heart

rate.

To determine the effect of cocaine on CNS structures that mediate sympathetic

nervous system outflow, three types of experiments were performed using

100
TABLE 3. Effects of cocaine administration on heart rate increases induced

by electrical stimulation of postganglionic cardiac sympathetic

nerves and by IV norepinephrine

SOURCE: Jain et al. 1990, copyright 1990, Williams and Wilkins.

anesthetized cats and dogs. The first was to administer cocaine into the

vertebral artery of anesthetized cats while monitoring mean arterial blood

pressure and heart rate. The second was to administer IV cocaine to

anesthetized cats while monitoring spontaneous discharge from postganglionic

cardiac sympathetic nerve fibers. The third was to compare in sedated dogs

the cardiovascular effects of IV cocaine to those elicited by an equimolar IV

dose of cocaine methiodide (a derivative of cocaine that does not cross the

blood-brain barrier).

lntravertebral administration of drugs results in their delivery primarily to

hindbrain structures (Van Zwieten 1975). Vertebral artery injection of 0.1, 0.3,

and 1.0 mg cocaine in anesthetized cats resulted in decreases in mean arterial

blood pressure of -24±7, -16±6, and -32±13 mmHg, respectively.

Corresponding changes in heart rate were -4±1, -17±5, and -66±21 beats/min,

respectively. To test the possibility that cocaine injected into the vertebral artery

might have produced hypotension and bradycardia by crossing from the CNS

into the peripheral circulation, the largest dose (1.0 mg) was administered by

the IV route; no significant effect on either blood pressure or heart rate

occurred.

101
FIGURE 3. Effect of repeated injection of cocaine on heart rate increases

produced by electrical stimulation of cardiac accelerator nerves in

an anesthetized, spinal cord transected cat. Control responses

were obtained at 0 and 6 minutes before cocaine administration.

Note enhanced response approximately 1 minute after cocaine

(i.e., at 12 minutes). The cocaine dose was repeated about 77

minutes, and no evidence of tachyphylaxis was noted with the low

dose of cocaine tested. Columns depict baseline levels (flat end)

immediately before nerve stimulation, and tips of arrows depict

maximal increase in heart rate during accelerator nerve

stimulation.

SOURCE: Jain et al. 1990, copyright 1990, Williams and Wilkins.

More direct evidence indicating an inhibitory effect of cocaine on central

sympathetic centers was obtained from five experiments in anesthetized cats in

which postganglionic sympathetic nerve activity was monitored during IV

administration of 2 mg/kg of cocaine. Mean arterial blood pressure and heart

rate also were monitored in these studies. IV injection of cocaine produced an

102
immediate reduction in integrated sympathetic nerve activity; the mean

reduction obtained in the five animals was 52±7 percent (p<0.05). However,

there were no accompanying significant decreases in either arterial blood

pressure (-7±8 mmHg) or heart rate (-11±10 beats/min).

Table 4 indicates the cardiovascular responses that were obtained in sedated

dogs when an IV dose of 2 mg/kg of cocaine and an equimolar IV dose of its

quaternary derivative, cocaine methiodide, were studied. Both compounds

produced essentially similar increases in blood pressure, heart rate, and cardiac

output; neither compound altered coronary blood flow. The qualitative and

quantitative similarities in the cardiovascular responses produced by these

agents, one of which does not penetrate the blood-brain barrier, provide further

evidence against an action of cocaine in the CNS to produce stimulation of

sympathetic centers.

TABLE 4. Comparative effects of cocaine and cocaine methiodide on several

indices of cardiovascular function in dogs

Indices of Cardiovascular Function Measured

Drug Tested

and Number of Mean Arterial

Animals Studied Experimental Heart Rate Blood Pressure Cardiac Output Coronary Blood

(mL/min/g) Conditions (beats/min) (mmHg) (L/min) Flow

Cocaine (N=7) Before cocaine 76±9 106±6 3.7±0.7 1.2±0.3

(2 mg/kg)

Maximum effect

of cocaine

117±24a160±17a6.1±2.0 2.6±0.9

Cocaine

methiodide

(N=6)

(2.65 mg/kg)

Before cocaine

methiodide

82±8 109± 2 3.4±0.4 0.6±0.0

Maximum effect

of cocaine

methiodide

136±11a152±12a4.6+0.3a1.0+0.3

Values=meane±SEM

a

p<0.05 using the Student’s t-test for paired data

SOURCE: Kuhn et al. 1988, copyright 1988, American Heart Association.

103
The role of the sympathetic nervous system effects of cocaine in the

cardiovascular responses produced by the drug was studied using anesthetized

dogs and cats. In the dog studies, the effect of alpha-adrenoceptor blockage

with phentolamine on the coronary circulatory changes produced by IV cocaine

(0.5, 1.0, and 2.0 mg/kg) was evaluated. In control dogs, the largest IV dose of

cocaine (2 mg/kg IV) was found to produce a decrease in the diameter of the

left anterior descending coronary artery of 19±3 percent (p<0.05) and an

increase in coronary vascular resistance of 55±20 percent (p<0.05). The

effects were noted 2 minutes after cocaine administration and were

accompanied by significant (p<0.05) increases in heart rate (from 76±9 to

100+14 beats/min), mean arterial blood pressure (from 106±6 to 128±10

mmHg), and cardiac output (from 3.7±0.7 to 5.4±1.7 L/min). The two lower

doses of cocaine (0.5 and 1.0 mg/kg IV) produced similar changes that were of

lesser magnitude. The deleterious effects of cocaine (2 mg/kg IV) on the

coronary circulation appeared to be due to alpha-adrenoceptor stimulation.

Evidence for this was that phentolamine pretreatment (2.5 mg/kg) prevented

cocaine-induced narrowing of the left anterior descending coronary artery and

increase in coronary vascular resistance. In addition, phentolaminepretreatment also counteracted the pressor effect of cocaine (Kuhn et al. 1990).

In the cat studies, the effect of blockade of alpha- and beta-adrenoceptors,

using phentolamine (5 mg/kg) and propranolol (0.75 mg/kg), respectively, was

evaluated on the blood pressure and myocardial conduction changes produced

by IV cocaine (0.25-4.0 mg/kg). In control cats, these doses of cocaine

produced increases in blood pressure and increases in the PR interval and the

QRS duration of the ECG (Bachenheimer et al. 1988). Doses of 2 and 4 mg/kg

resulted in intraventricular conduction defects, secondary and tertiary heart

block, and isolated premature ventricular contractions (Bachenheimer et al.

1988). The rhythm disturbances and the prolongation of the ECG intervals

were dose-related (Bachenheimer et al. 1988). Tachyphylaxis was observed to

occur to the pressor effect of cocaine, 2 mg/kg IV. Initial administration of this

dose increased the mean arterial blood pressure by 24±6 percent (p<0.05).

Upon repeating the 2 mg/kg dose five times, the mean arterial blood pressure

response for the fifth administration of cocaine was 0±10 percent. Furthermore,

the pressor response observed with the initial 2.0 mg/kg dose was absent in

animals pretreated with a combination of phentolamine and propranolol.

Indeed, 2 mg/kg cocaine IV, administered after adrenergic blockade, produced

a decrease in arterial blood pressure of 34±19 percent.

In terms of the effect of cocaine on QRS duration, tachyphylaxis was not

observed to cocaine-induced prolongation of this interval (QRS duration

increased by +83±15 percent with 2 mg/kg given as a first dose vs. an increase

104
of +92±31 percent after administration of a fifth dose), and pretreatment with

adrenergic blocking agents did not counteract cocaine-induced prolongation of

the QRS duration. In control animals, cocaine 2 mg/kg IV prolonged QRS

duration by +83±15 percent as indicated above. The corresponding value after

adrenergic blockade was +156±17 percent.

DISCUSSION

Data from our studies provide the following evidence that sympathomimetic

effects of cocaine are only due to a peripheral site of action of the drug: (1)

cocaine given IV to cats with transacted spinal cord potentiates the chronotropic

response to sympathetic nerve stimulation; (2) cocaine methiodide, a

quaternary analog of cocaine, produces cardiovascular effects in dogs similar to

those evoked by cocaine; (3) cocaine does not produce increases in heart rate

or blood pressure after vertebral artery administration; and (4) cocaine does not

increase spontaneously occurring sympathetic nerve discharge after IV

administration. Presumably, this peripheral sympathomimetic effect of cocaine

was due to the well-known action of this agent to inhibit the neuronal uptake of

norepinephrine.

Focusing on these peripheral effects of cocaine, the degree of potentiation was

related linearly to dose over the range of 0.0625 to 0.25 mg/kg and then began

to decline as the dose was increased further. The time course for potentiation

followed a consistent pattern, with maximal enhancement in response occurring

immediately after cocaine administration; the enhanced response then

dissipated rapidly and was usually gone within 1 hour after cocaine

administration. Tachyphylaxis developed to the cocaine-induced potentiation of

the response to cardiac sympathetic nerve stimulation.

These findings also indicate that cocaine can potentiate cardiovascular

responses to injected norepinephrine. Potentiation occurred with low and high

doses of cocaine tested. Unlike the situation with neurally released

norepinephrine, no falloff in cocaine-induced potentiation of injected

norepinephrine was observed, which suggests that the falloff in the potentiated

response with nerve stimulation was due to a local anesthetic effect of cocaine.

Consistent with this notion are the findings of Yasuda and colleagues (1984),

which demonstrate that local anesthetic effects of cocaine become manifest at

dose levels about 10 times higher than the dose required for inhibition of

norepinephrine at nerve terminals. That is, we observed maximal potentiation

with 0.25 mg/kg, and this “potentiation” was canceled out with the 2.0 mg/kg

dose of cocaine.

In terms of the role of the peripheral sympathomimetic action of cocaine on the

cardiovascular responses seen with this drug, it is clear from our studies that

105
the following responses evoked by cocaine are mediated by the sympathetic

nervous system: (1) narrowing of the lumen of the coronary epicardial vessels

in dogs, (2) increase in resistance of the coronary arterioles in dogs, and (3)

increase in systemic arterial pressure in dogs and cats. All these effects were

blocked by pharmacological agents that competitively antagonize

norepinephrine on postsynaptic receptors. Since tachyphylaxis was observed

with cocaine-induced inhibition of norepinephrine uptake, it was not unexpected

that this effect would be observed with the pressor effect of IV cocaine. As

pointed out In the results section, repeated administration of cocaine to

anesthetized cats resulted in diminishing effects on blood pressure. This was in

contrast to cocaine-induced increases in the PR interval and the QRS duration

of the ECG. Tachyphylaxis was not observed to occur to this effect

(Bachenheimer et al. 1988).

With regard to cocaine’s action in the CNS, we observed only

sympathoinhibitory effects on blood pressure, heart rate, and spontaneously

occurring sympathetic nerve discharge. Preliminary experiments performed in

our laboratory on decerebrate unanesthetized cats also indicate an effect of

cocaine to depress spontaneously occurring sympathetic nerve discharge

(Raczkowski et al., In press). A possible reason for this inhibitory effect on

sympathetic nerve discharge may be that, as in the periphery, cocaine is

inhibiting the uptake of catecholamines at CNS sites controlling sympathetic

outflow. Central administration of catecholamines is known to inhibit

sympathetic outflow (De Jong 1974). Thus, blockade of catecholamine uptake

in the periphery and in the CNS produce opposing effects on sympathetic

nervous system function, with the peripheral sympathomimetic effects of

cocaine predominating on administration of doses of cocaine used initially for

recreational purposes. Since tachyphylaxis occurs to the peripheral

sympathomimetic effects of cocaine and since the pattern of use of this drug

involves repeated administration of increasing doses, the serious cardiovascular

complications associated with cocaine may be due to the direct effects of the

drug on cardiac conduction and contractility. The peripheral sympathomimetic

effects of cocaine initially may counteract the direct deleterious effects of

cocaine on cardiac conduction (conduction is slowed) and force of contraction

(force is decreased). However, once tachyphylaxis occurs to the

sympathomimetic effects, the direct effects on the heart, to which tachyphylaxis

does not occur, ultimately may prevail and result in death. Finally, at this point

during cocaine administration, cocaine-induced central sympathoinhibition

would be manifested fully as well since it would not be offset by the peripheral

potentiating effects of cocaine. Thus, once tachyphylaxis occurs to cocaine, the

direct myocardial effects of the drug as well as centrally mediated inhibition of

sympathetic outflow could lead to cardiovascular collapse and death.

106
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AIken, J.W., and Reit, E. Stimulation of the cat stellate ganglion by anglotensin.

J Pharmacol Exp Ther 159:107-114, 1968.

Bachenheimer, L.C.; Tracy, C.M.; Visner, M.S.; and Gillis, R.A. Mechanism of

cocaine associated cardiotoxlcity. Circulation 78(4):11-359, 1988.

Chiueh, C.C., and Kopin, I.J. Centrally mediated release by cocaine of

endogenous epinephrine and norepinephrine from the sympathoadrenal

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154,1978.

De Jong, W. Noradrenaline; central inhibitory control of blood pressure and

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Fischman, M.W.; Schuster, C.R.; Javaid, C.R.; Hatano, V.; and Davis, J. Acute

tolerance development to the cardiovascular and subjective effects of

cocaine. J Phamracol Exp Ther 235:677-682, 1985.

Hale, S.L.; Alker, K.J.; and Kloner, R.A. Evaluation of nonradioactive, colored

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elicited by sympathetic nerve stimulation. J Pharmacol Exp Ther 252:147-

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Johnson, G.L., and Kahn, J.B., Jr. Cocaine and antihistaminic compounds:

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Juhasz-Nagy, A., and Szentivanyi, M. Separation of cardioaccelerator and

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Kuhn, F.E.; Gillis, R.A.; Wahlstrom, S.K.; Tessel, R.E.; Visner, M.S.; and

Schaer, G.L. Cocaine-induced cardiovascular effects: Lack of evidence for

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Kuhn, F.E.; Johnson, M.N.; Gillis, R.A.; Visner, M.S.; and Schaer, G.L. The

effect of cocaine on the coronary circulation and systemic hemodynamics in

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Levy, M.N., and Blattberg, B. Progressive reduction in norepinephrine overflow

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Levy, M.N., and Blattberg, B. The influence of cocaine and desipramine on the

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Pappas, N.; Margolius, H.S.; and Gaffney, T.E. The influence of cocaine on the

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ACKNOWLEDGMENT

This work was supported by National Institutes of Health grant R01 DA-05333.

AUTHORS

Richard A. Gillis, Ph.D.

Professor of Pharmacology

Department of Pharmacology

Lisa C. Bachenheimer, M.D.

Resident in Anesthesiology

Department of Anesthesiology

Kenneth L. Dretchen, Ph.D.

Professor of Pharmacology

Department of Pharmacology

108
Hashim K. Erzouki, M.D.

Yvonne M. Hernandez, Ph.D.

Research Instructor in Pharmacology

Department of Pharmacology

Rakesh K. Jain, M.D.

Fellow in Cardiology

Department of Medicine

Georgetown University School of Medicine

3900 Reservoir Road, N.W.

Washington, DC 20007

Muskesh K. Jain, B.S.

State University of New York at Buffalo

102 Farber Hall

Buffalo, NY 14214

Fred E. Kuhn, M.D.

Assistant Professor of Medicine-Cardiology

Department of Medicine

Georgetown University School of Medicine

3900 Reservoir Road, N.W.

Washington, DC 20007

Jack Quest, Ph.D.

Head

Science Support Section

Health Effects Division

H7509C

Environmental Protection Agency

401 M Street, S.W.

Washington, DC 20480

Gary L. Schaer, M.D.

Assistant Professor of Medicine—Cardiology

Department of Medicine

Rush-Presbyterian-St. Luke’s Medical Center

Chicago, IL 60612

109
Cocaine-Induced Myocardial

Depression

Theodore D. Fraker, Jr., Peter N. Temesy-Armos,

and R. Douglas Wilkerson

INTRODUCTION

The cardiovascular effects of cocaine are complex, diverse, and sometimes

divergent in their biologic activity. Because cocaine is a local anesthetic, it

shares the membrane-depressant effects, and hence negative inotropic effects,

of other local anesthetics (e.g., procainamide). Unlike other local anesthetic

agents, however, cocaine has the unique ability to block neuronal reuptake of

biogenic amines, including norepinephrine. This latter effect leads to adrenergic

stimulation and activation of cardiac beta receptors, producing an augmented

inotropic state. Which of these two effects—the local anesthetic/negative

inotropic effect or the adrenergic stimulation/positive inotropic effect—

predominates in humans after recreational cocaine use is unknown, Adding to

the complexity of the myocardial function issue is the possibility that cocaine

may cause focal coronary artery spasm or diffuse coronary artery

vasoconstriction. Either effect could result in depressed regional myocardial

function indirectly via myocardial ischemia. This chapter focuses on negative

inotropism caused by cocaine in isolated muscle preparations, in sedated but

intact dogs, in conscious dogs, and in humans.

ISOLATED MUSCLE PREPARATIONS

Herman and Vick (1987) studied the direct effect of cocaine on isolated, bloodperfused Langendorff dog hearts. Doses of less than 1 mg of cocaine injected

directly into a 500 mL coronary circulation produced variable effects on heart

rate and force of contraction. Doses of 2 to 25 mg of cocaine thus injected

decreased both heart rate and force of contraction. A dose of 50 mg of cocaine

resulted in cardiac arrest. Morcos and coworkers (1988) studied the direct

effect of cocaine on isolated rabbit ventricular septa maintained in an

oxygenated Krebs solution. Perfusion of these septa with 10-5, 10-4, and 10-3

molar cocaine concentrations resulted in progressively increased depression of

developed tension, rate of tension development, and rate of tension relaxation.

110
Excitation-contraction decoupling, occurring at all doses, was seen in 100

percent of paced beats at the 10-3 molar concentration. These effects were

rapidly reversed after washout of cocaine. Although these two reports were

preliminary, both are consistent with a direct negative inotropic effect of cocaine

on the myocardium.

SEDATED DOG PREPARATIONS

Bedotto and colleagues (1988) have done extensive studies in mongrel dogs

during diazepam and hydromorphone sedation. These animals were

instrumented previously with pulmonary artery, aortic, and left ventricular

catheters. During a cocaine infusion of 0.5 mg/kg per minute, hemodynamic

variables were measured. Cocaine caused significant increases in mean aortic

pressure and systemic vascular resistance. Heart rate and pulmonary artery

pressure rose modestly but not significantly. A negative inotropic effect of

cocaine was suggested by a modest but nonsignificant fall in left ventricular dp/

dt. A significant decrease occurred in cardiac index (measured by

thermodilution) and in left ventricular ejection fraction from 0.61 to 0.49

(determined by contrast angiography). Proximal and distal coronary artery

diameters (left anterior descending artery) were unchanged by cocaine: thus, it

seemed unlikely that the negative inotropic effect was due to an ischemic

mechanism. Wilson and colleagues (1988) studied eight pentobarbitalanesthetized, open-chest dogs subjected to contrast arterial pressure and heart

rate. Large doses of cocaine (>100 mg) caused significant depression of dp/dt

and an increase in left ventricular end-diastolic pressure. Coronary sinus blood

flow, circumflex artery flow, and myocardial atrioventricular oxygen difference

were measured and found to be unaffected by cocaine. These data also

suggest a direct depressant effect of cocaine on the myocardium. Other data

(Hale et al. 1989) differ somewhat from that described above. Pentobarbitalanesthetized dogs were studied after a bolus injection of 10 mg/kg of cocaine;

15 minutes later, heart rate and left ventricular dp/dt were significantly reduced

compared with baseline. Left ventricular size (by echocardiography) was

significantly increased, and subepicardial blood flow was reduced by more than

25 percent. Another group of animals was studied 3 to 5 minutes after injection

of 10 mg/kg of cocaine. Angiographic coronary artery diameters were

decreased by 15±4 percent, and regional epicardial blood flow again fell by

about 25 percent. These data suggest that myocardial ischemia caused by

coronary artery vasoconstriction may play a role in cocaine-induced left

ventricular depression.

CONSCIOUS DOGS

Studies on the effects of cocaine in conscious dogs have been reported only

from our laboratory (Fraker et al. 1989). Our model uses conditioned mongrel

111
dogs that are trained to lie quietly on a raised nylon mesh support stand. This

stand allows access to the dog’s right parasternal chest with an

echocardiographic transducer while the animal is lying on its right side. Animals

that cooperate with the echo examination become the subjects of study. Each

animal undergoes implantation of a Doppler coronary blood flow probe (on the

circumflex coronary artery), an arterial catheter, and a left atrial catheter during

general anesthesia. This technique has been shown to preserve the

innervation of the circumflex vascular bed (Knight et al. 1987). After a P-week

recovery and training period, the animals are ready for study.

We evaluated left ventricular function by measuring the systolic/diastolic change

in the area of the short axis view of the midleft ventricle obtained by twodimensional echocardiography. In this study, the left ventricle looks roughly like

a donut. The circumference of the left ventricle is split almost equally between

the distribution of the circumflex coronary artery and the left anterior descending

coronary artery. Measurement of the change in the area of the left ventricular

cavity from systole to diastole is called the regional (i.e., mid left ventricular)

ejection fraction and is roughly equivalent to an ejection fraction obtained by

contrast left ventricular angiography, presuming that the mid left ventricle

behaves in a way representative of the whole left ventricle.

The animal is positioned without sedation on the nylon mesh support, and the

echo transducer is positioned at the right parasternal edge below the support,

Baseline echocardiographic imaging is recorded continuously on videotape.

Simultaneous measurements of circumflex artery blood flow, heart rate, and

blood pressure also are recorded. After a period of stable baseline recording,

the animal is given cocaine as a bolus injection into the left atrial catheter. The

echocardiographic imaging and hemodynamic recordings are continued for the

next 10 to 15 minutes.

At doses of 1 mg/kg of cocaine (four dogs), very little effect on regional ejection

fraction was observed by echo. As expected, heart rate and blood pressure

rose acutely, peaking at 1 to 2 minutes after cocaine. The rate pressure

product (heart rate x systolic blood pressure) was increased by 20 percent at 1

minute, and coronary blood flow was increased by 23 percent. At a dose of 4

mg/kg of cocaine (eight dogs), the cardiovascular responses were very

different. Midleft ventricular ejection fraction fell by 47 percent at 1 minute after

cocaine. By 10 minutes, the ejection fraction was only 15 percent below

baseline values. At 1 minute after cocaine, the rate-pressure product was 93

percent above baseline values, while coronary blood flow was increased by 38

percent. Calculated coronary resistance actually rose despite the high

metabolic demand imposed by the dramatic increase in heart rate and blood

pressure. At 10 minutes after cocaine, the rate-pressure product was still 70

112
percent above baseline: coronary blood flow was 23 percent above baseline;

yet left ventricular function had largely recovered. At no time did we observe

segmental wall motion abnormalities of the left ventricle in either the circumflex

or anterior descending vascular beds.

There are several interesting aspects to these data. First, global left ventricular

function is dramatically reduced in conscious dogs given 4 mg/kg of cocaine

despite abundant hemodynamic evidence of intense adrenergic stimulation.

Second, the depression In global left ventricular function appears to be very

transient, at least in this model. Third, even though there is indirect evidence of

coronary vasoconstriction after cocaine administration, It seems unlikely that

ischemia plays a major role in the depression of left ventricular function

because the left ventricle recovers rapidly despite more prolonged

hemodynamic effects of adrenergic stimulation. We believe that direct

membrane depression is largely responsible for depressed myocardial function,

an effect that occurs in conscious animals despite high levels of adrenergic

tone.

HUMAN STUDIES

There are no studies on the myocardial depressant effect of cocaine in humans.

Although sudden death has been temporally associated with cocaine use in

many reported cases, a variety of other mechanisms have been proposed,

including acute myocardial infarction (Isner et al. 1986), ventricular arrhythmias

(Inoue and Zipes 1988), and respiratory depression (Catravas et al. 1978).

Germane to a discussion of myocardlal depression Is a single case report by

Allred and Ewer (1981). A 36-year-old man developed severe dyspnea

immediately after injecting freebase cocaine intravenously. Clinical and

radiographic examinations were consistent with acute pulmonary edema. The

patient died 3 hours later despite vigorous medical therapy. The time course of

events in this case is consistent with the acute myocardial depressant effect of

cocaine seen in animal studies. Whether this effect of cocaine plays a major

role in cocaine-related sudden deaths remains to be proven.

CONCLUSIONS

Cocaine causes acute, severe, but transient depression of global left ventricular

function in laboratory animals and probably in humans. This effect occurs

despite intense adrenergic nervous system stimulation due to blockade of

neuronal uptake of norepinephrine. The importance of this effect in those

patients who die suddenly after cocaine ingestion remains unclear.

113
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circulation. J Am Coll Cardiol 11:1337-1342, 1988.

Catravas, J.D.; Waters, I.W.; Walz, M.A.; and Davis, W.M. Acute cocaine

intoxication in the conscious dog: Pathophysiologic profile of acute lethality.

Arch Int Pharmacodyn 235:328-340, 1978.

Fraker, T.; Temesy-Armos, P.; and Wilkerson, R. Cocaine causes transient

myocardial depression in conscious dogs. J Mol Cell Cardiol 21 [Suppl II]:S196, 1989.

Hale, S.L.; Alker, K.J.; Rezkalla, S.; Figures, G.; and Kloner, R.A. Adverse

effects of cocaine on cardiovascular dynamics, myocardial blood flow, and

coronary artery diameter in an experimental model. Am Heart J 118:927-

933,1989.

Herman, E.H., and Vick, J. A study of direct effect of cocaine on the heart. Fed

Proc 46:1146, 1987.

Inoue, H., and Zipes, D.P. Cocaine-induced supersensitivity and

arrhythmogenesis. J Am Coll Cardiol 11:867-874, 1988.

Isner, J.M.; Estes, N.A.M.; Thompson, P.D.; Costanzo-Nordin, M.R.;

Subramanian, R.; Miller, G.; Katsas, G.; Sweeney, K.; and Sturner, W.Q.

Acute cardiac events temporally related to cocaine abuse. N Engl J Med

315:1438-1443, 1986.

Knight, D.R.; Thomas, J.X.; Randell, W.C.; and Vatner, S.F. Effects of left

circumflex coronary flow transducer implantation on posterior wall

innervation. Am J Physiol 252:H536-H539, 1987.

Morcos, N.C.; Fairhurst, A.S.; and Henry, W.L. Direct but reversible effects of

cocaine on the myocardium. J Am Coll Cardiol 11:71A, 1988.

Wilson, S.P.; Abel, F.L.; Zhao, R.R.; and Fennell, W.H. Cocaine is a myocardial

depressant. FASEB J 2:A1817, 1988.

ACKNOWLEDGMENT

This work was supported by National Institute on Drug Abuse contract 271-87-

8130.

AUTHORS

Theodore D. Fraker, Jr., M.D.

Associate Professor of Medicine

114
Peter N. Temesy-Armos, M.D.

Associate Professor of Medicine

Division of Cardiology

Department of Medicine

R. Douglas Wilkerson, Ph.D.

Professor of Pharmacology

Department of Pharmacology

The Medical College of Ohio

P.O. Box 10008

Toledo, OH 43899

115
Prevalence of Myocardial lschemia in

Cocaine Addicts

Koonlawee Nademanee

INTRODUCTION

Americans have watched the number of cocaine users and cocaine-related

cardiovascular diseases rise in the past 10 years (Isner et al. 1986; Cregler and

Mark 1986). Around 1983, when the drug became readily available in stronger

form, the trend toward prevalent cocaine abuse escalated sharply. Alerted by

the increasing number of young cocaine users admitted to emergency rooms,

the medical community began to examine the phenomenon of cocaine-related

myocardial ischemic syndromes. In the past, coronary syndromes usually were

limited to older patients who had coronary artery disease, but now some

younger people who abuse cocaine are experiencing serious myocardial

ischemic disorders.

Cocaine blocks the presynaptic reuptake of catecholamines, causing an

increase in norepinephrine, epinephrine, and dopamine in the synapses and the

circulation (Rathke and Green 1985). This stimulates sympathetic activity,

which increases heart rate, blood pressure, and in turn myocardial oxygen

demand (Resnick et al. 1977). Cocaine also enhances platelet and thrombus

formation (Togna et al. 1985) and produces coronary vasoconstriction and

vasospasm (Zimmerman et al. 1987). From these pharmacological effects, one

can infer that addicts who chronically abuse cocaine face a great risk of

developing myocardial ischemia or myocardial infarction and that those addicts

who have a diseased substrate face an even greater risk. Since the incidence

of ischemic syndromes among cocaine addicts had not yet been investigated,

we initiated a prospective study to determine the nature and prevalence of

myocardial ischemia in cocaine addicts. In this review we describe the

preliminary results of our study.

PATIENT POPULATION

The study used 63 male cocaine addict patients (mean age, 34 years) who

were enrolled in a 28-day inpatient substance abuse treatment program. Of the

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63 patients, 62 smoked freebase: of those, 9 also used the drug intranasally, 1

intravenously, and 1 intravenously and intranasally (mean duration of cocaine

use=5.17 years). After giving written informed consent, subjects underwent

cardiac testing as soon as possible after admission and again just before

discharge.

ECG ABNORMALITIES

We found that chronic cocaine users had a markedly high incidence of

electrocardiogram (ECG) abnormalities (31 percent), usually manifesting as ST

abnormalities (14 percent). Almost half the patients had chest pain, which

markedly decreased after they were admitted to the hospital. This pain was not

typical of angina, and its etiology was not known. However, because several

patients had chest pain in the presence of ST changes, one cannot rule out

myocarditis or the sequelae of myocardial ischemia as a cause of the pain or

ST changes.

INCIDENCE OF MYOCARDIAL ISCHEMIA: HOLTER MONITORING VS.

EXERCISE TREADMILL TESTING

Of these 63 patients, 21 consecutive male chronic cocaine addicts (mean age,

34±6 years) were analyzed to determine the prevalence of spontaneous and

exercise-induced myocardial ischemia (Nademanee et al. 1989). A serial 24-

hour electrocardiographic ambulatory (Holter) monitoring and exercise treadmill

testing were used to detect the incidence of myocardial ischemia. Both tests

were performed as soon as possible after admission and again just before

discharge. All 21 patients had their first Holter monitoring during the first 2

weeks after admission to the program. The interval between the last dose of

cocaine and the first Holter monitoring varied considerably among patients

because there was no control over when the patients chose to enter the study

after their last dose of cocaine. Of the 21 initial Holter tapes recorded, 4 were

unanalyzable for various reasons (e.g., mechanical failure or early removal of

electrodes by patients). Sixteen patients had a second Holter within 3 to 4

weeks after admission, and 5 of these patients had another Holter 6 to 12

weeks after admission.

All Holter tapes were coded, scanned blindly, and mixed with those of 42

normal volunteers and 119 patients with angina (70 chronic stable and 49

unstable angina patients). None of the volunteers (age 28.7±3.6 years) had a

history of heart disease or coronary risk factors.

A significantly greater proportion of cocaine addict patients had episodes of ST

elevation compared with normal volunteers. Eight of the 21 patients had a total

117
of 45 ST elevation episodes (range=1-13 episodes per 24-hour period;

mean=5.6 episodes). The mean duration per episode was 57±77 minutes

(range=1-362 minutes). These episodes occurred even though the patients had

not used cocaine during Holter monitoring; abstinence was verified by negative

urine drug assays. Forty-five percent of the patients had ST changes on Holter

during the first week; 25 percent had ST changes during the second week; 28

percent had ST changes during the third week; and 11 percent had ST changes

during the fourth week. However, there were no ischemic episodes after a

longer withdrawal period (8 weeks) from the drug.

The ST changes of the cocaine addict patients were similar to episodes of ST

elevation of Prinzmetal’s angina patients. In contrast, none of the volunteers

and chronic stable angina patients and only 4 percent of the unstable angina

patients had ST elevation episodes on Holter (cocaine vs. volunteers; p=.0004).

This observation suggests that cocaine users faced a significantly greater risk of

developing ST changes than the healthy volunteers (relative risk=16). Thus,

chronic cocaine users may be at risk of developing myocardial ischemia

precipitated by coronary vasospasm even after they stop using the drug

Only 1 of the 20 cocaine addict patients had a positive exercise test for

ischemia. Very few cocaine addict patients had exercise-induced ischemia,

indicating that most did not have significant coronary artery obstruction. In line

with this, only 3 of the 42 volunteers had ST changes characteristic of

myocardial ischemia during exercise treadmill testing. There was a significant

difference between the peak exercise blood pressure response to exercise in

the exercise treadmill test of the first visit and that of the second visit. The peak

exercise blood pressure was significantly higher at the first visit within the first

week after admission and last dose of cocaine than at the second visit 3 weeks

later--despite the fact that there was no difference in resting blood pressure

between the two visits. The mean resting blood pressure during the first and

second visits was 115±11 and 112±11 mmHg, respectively, whereas the peak

exercise blood pressure of first and second visits was 177±22 and 185±20

mmHg, respectively (p<.01). This finding suggests that soon after cocaine

withdrawal the patient’s blood pressure may have risen (i.e., in response to

exercise) and then reverted back toward baseline after a longer period of

abstinence from the drug.

These observations suggest that chronic cocaine use may make the coronary

arteries more vulnerable to vasospasm, an effect that lingers even during

withdrawal. This may be because chronic cocaine use creates a dopaminedeficient state. Dopamine, a powerful coronary vasodilator, stimulates the

dopamine receptors in the coronary arteries and inhibits the norepinephrine

release at the presynaptic junction (Goldberg and Rajfer 1985). Thus, the

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consequent lack of dopamine could lower the threshold for coronary spasm and

enhance norepinephrine release. The finding that cocaine addicts had an

exaggerated blood pressure response to exercise immediately after withdrawal

suggests that chronic cocaine use may heighten sensitivity to adrenergic

receptor stimulation. Several studies have shown that long-term use of

stimulants causes the central dopaminergic, alpha-adrenergic, and betaadrenergic receptors to become supersensitive (Gawin and Kleber 1986).

These studies show that the primary neurophysiologic substrate of cocaine

withdrawal is supersensitivity of the inhibitory receptors on the dopamine

neuron (autoreceptors); this heightened sensitivity reduces dopaminergic

neurotransmission. Chronic cocaine use, by causing dopamine depletion, could

sensitize alpha-adrenergic receptor stimulation, thus lowering the threshold for

vasospasm.

SUMMARY

The finding that most young cocaine addict patients had a negative exercise

treadmill test suggests that they did not have preexisting obstructive coronary

artery disease. Noninvasive testing did show, however, that these patients

frequently had a high incidence of ST elevation episodes during the first 2

weeks of withdrawal. The pathophysiological mechanism of cocaine-induced

cardiovascular disease is not yet clearly understood, but it is probably more

complex than the drug’s acute direct effects on the cardiovascular system. It

may be complicated by fluctuations in catecholamine homeostasis and further

temporally complicated by cycles of cocaine use and withdrawal. Research on

how cocaine use alters catecholamine homeostasis will increase the

understanding of the pathophysiology of cocaine and assist in developing

effective pharmacologic and prophylactic treatment for its abuse.

REFERENCES

Cregler, L.L., and Mark, H. Medical complications of cocaine abuse. N Engl J

Med 315:1495-1500, 1986.

Gawin, F.H., and Kleber, H.D. Abstinence symptomatology and psychiatric

diagnosis in cocaine abusers. Arch Gen Psychiatry 43:107-113, 1986.

Goldberg, L.I., and Rajfer, S.I. Dopamine receptor: Applications in clinical

cardiology. Circulation 72:245-248, 1985.

Isner, J.M.; Estes, N.A.M. III; Thompson, P.D.; Costanzo-Nordin, M.R.;

Subramanian, R.; Miller, G.; Katsas, G.; Sweeney, K.; and Sturner, W.Q.

Acute cardiac events temporally related to cocaine use. N Engl J Med

315:1438-1443, 1986.

119
Nademanee, K.; Gorelick, D.A.; Josephson, M.A.; Ryan, M.A.; Wilkins, J.N.;

Robertson, H.A.; Mody, F.V.; and Intarachot, V. Myocardial ischemla during

cocaine withdrawal. Ann lntern Med 111(11):878-880, 1989.

Rathke, J.M., and Green, N.M. Local anesthetics. In: Gilman, A.G.; Goodman,

L.S.; Rall, T.W.; and Murad, F., eds. The Pharmacologic Basis of

Therapeutics. 7th ed. New York: MacMillan, 1985. pp. 309-310.

Resnick, R.B.; Kestenbaum, R.S.; and Schwartz, L.K. Acute systemic effects of

cocaine in man: A controlled study by intranasal and intravenous routes.

Science 195:898-898, 1977.

Togna, G.; Tempesta, E.; Togna, A.R.; Dolci, N.; Cebo, B.; and Caprino, L.

Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in

response to in vitro cocaine treatment. Haemostasis 15(2):100-107, 1985.

Zimmerman, F.H.; Gustafson, G.M.; and Kemp, H.G., Jr. Recurrent myocardial

infarction associated with cocaine abuse in a young man with normal

coronary arteries: Evidence for coronary artery spasm culminating in

thrombosis. J Am Coll Cardiol 91:984-988, 1987.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grant DA-05485-C1

and American Heart Association grant-in-aid 789G1-3.

AUTHOR

Koonlawee Nademanee, M.D.

Chief

Cardiology Division

Denver General Hospital

Mail Code 0940

777 Bannock Street

Denver, CO 80204-4507

120
Cocaine-Induced Myocardial

Infarction: Clinical Observations

and Pathogenetic Considerations

Jeffrey M. lsner and Saurabh K. Chokshi

CLINICAL OBSERVATIONS

Among the alleged cardiac consequences of cocaine abuse, the one reported

most frequently is acute myocardial infarction (Coleman et al. 1982; Schachne

et al. 1984; Kossowsky and Lyon 1984; Pasternack et al. 1985; Howard et al.

1985; Cregler and Mark 1985; Gould et al. 1985; Wilkins et al. 1985; Weiss

1986; Simpson and Edwards 1986; Rollinger et al. 1986; lsner et al. 1985;

Mittleman and Wetli 1987; Rod and Zucker 1987; Zimmerman et al. 1987; Smith

et al. 1987; Ascher et al. 1988; Virmani et al. 1988; lsner and Chokshi 1989).

At least 58 cases of acute myocardial infarction temporally related to cocaine

abuse have been reported in the English-language literature. The 58

individuals had a mean age of 32.8 years, ranging from 19 to 44 years; 49 were

male and 9 were female, perhaps a reflection of the demographics of cocaine

abuse. Only 3 of these 58 individuals were first-time cocaine users; the

remainder used cocaine on a chronic basis. Various routes of cocaine

administration related to acute infarction were identified: intranasal in 38,

intravenous in 17, freebase/mixed form in 2, and smoking in 1. A history of

preexisting angina or prior myocardial infarction unrelated to cocaine abuse was

positive in 18 of the 58 individuals; the 40 remaining persons had no antecedent

cardiac history. Seven of the 58 (12 percent) individuals died as a complication

of acute infarction.

The results of selective coronary angiography have been reported for 45 of

these 58 patients. In 31 cases, filling defects involving the infarct-related major

epicardial coronary arteries were observed, including occlusive lesions as well

as focal stenoses. lntraluminal filling defects inferred to represent intracoronary

thrombi were documented in 10 of 31 patients who received thrombolytic

therapy (either streptokinase or tissue plasminogen activator) within 8 hours of

onset of symptoms of acute infarction. Thrombolytic therapy was successful in

lysing the clot and reestablishing patency of the “culprit” artery in all of these

121
cases. In contrast, 14 of 45 patients (31 percent) were found to have

angiographically normal epicardial coronary arteries; although 8 of these 14

patients underwent ergonovlne provocative testing, all 8 failed to develop

angiographic evidence of focal coronary narrowing.

In one additional patient studied in our laboratory, cocaine was employed as the

provocative agent. No focal angiographic narrowing was observed following

standard provocation with intravenously administered ergonovlne. Following

serial nasal inhalation of 1 g of cocaine, heart rate and blood pressure

increased: coronary angiography disclosed focal coronary arterial spasm limited

to the proximal-most portion of the right coronary artery, Immediately distal to

the catheter tip. Although catheter-induced spasm could not be ruled out in this

patient, it is intriguing to note that no such focal spasm was observed during

rlght coronary angiography before cocaine provocation.

PATHOLOGIC OBSERVATIONS

The finding of lntracoronary thrombus in cases of myocardial Infarction related

to cocaine abuse has been confirmed in multiple cases studied at necropsy.

We previously described a 37-year-old man in whom cocaine-related acute

infarction was associated with thrombotic occlusion of the left anterior

descending coronary artery at the site of 90-percent cross-sectional area

narrowing by atherosclerotic plaque (Isner et al. 1985). Simpson and Edwards

(1996) observed platelet thrombi in one or more major coronary arteries of a 21-

year-old cocaine user who died suddenly and at necropsy was found to have

“microfocal areas of fibrosis or granulation tissue . . . interpreted to be ischemic

in origin.” Each of the major epicardial coronary arteries was severely narrowed

by 50 to 95 percent in cross-sectional area. Mittleman and Wetli (1987)

reported 24 cases of sudden death associated with cocaine abuse and

attributed the etiology in 15 of these to ischemic heart disease. Two victims had

evidence of acute infarction, and 10 others had gross or histologic findings of

myocardial fibrosis. Complete thrombotic occlusion of one epicardial coronary

artery was observed in three cases, while hemorrhage into an atherosclerotic

plaque was observed in two. All cases were notable for the presence of severe

focal arterial narrowing by atherosclerotic plaque in at least one major epicardial

coronary artery.

Virmani and colleagues (1988) studied two individuals at necropsy in whom

there was “severe coronary atherosclerosis” and another in whom an occlusive

platelet thrombus in the left anterior descending coronary artery was

superimposed on atherosclerotic plaque that had narrowed the native lumen by

40 percent in cross-sectional area. Likewise, Stenberg and coworkers (1989)

observed underlying atherosclerotic plaque that narrowed the left anterior

122
descending and right coronary arteries by 70 and 50 percent respectively in a

38-year-old man who died 13 hours after the onset of a clinically documented

acute myocardial infarctlon.

Finally, Dressler and colleagues (1990) reported quantitative analysis of

coronary arterial narrowing by atherosclerotic plaque among 22 chronic cocaine

users studied at necropsy over a 10-year period, Of the 12 individuals in whom

death was believed to be related to cocaine, at least one major epicardial

coronary artery was narrowed by more than 98 percent. In six cases, at least

one artery was narrowed by 78 to 95 percent; 51- to 75-percent cross-sectional

area narrowing was observed in ail but four cases. In 1 of these 12 cases,

intracoronary thrombus was superimposed on underlying atherosclerotic

plaque; in this and 2 others of the 12 cases, examlnation of the myocardium

disclosed microscopic foci of necrosis.

Although these necropsy studies of cocaine users whose death was attributed

to a cardiovascular etiology typically have disclosed more extensive coronary

narrowing by atherosclerotic plaque than has been suggested by premortem

angiographic assessment of such individuals, certain methodologic differences

among these various studies must be made explicit. The first difference

concerns the diagnosis of acute infarction. The majority of individuals studied

angiographically have had clinically documented acute myocardial infarction. In

contrast, most individuals described at necropsy have had neither myocardial

(confluent areas of coagulation necrosis) nor coronary (intracoronary thrombus)

evidence of acute myocardial infarction. It is possible that the individuals

studied at necropsy died from a nonischemic etiology; alternatively, these

individuals may have died before there was sufficient time for myocardial

necrosis to become evident and/or after spontaneous lysis of intracoronary clot.

The second difference concerns documentation of coronary arterial narrowing.

It is conceivable that premortem angiographic studies of patients with cocainerelated infarction have underestimated (Isner and Donaldson 1984) the degree

of underlying atherosclerotic narrowing compared with that observed in

necropsy studies; this is particularly feasible with regard to mild disease (less

than 50-percent cross-sectional area narrowing). Necropsy studies, on the

other hand, are complicated by the inherent bias involved in selecting out only

those individuals in whom the cocaine-related infarction was fatal. This latter

observation may be a contributing factor to the suggestion that chronic cocaine

use may accelerate coronary arterial narrowing (Dressler et al. 1990).

Independent of the quantitative aspect of coronary arterial narrowing in these

cocaine users, It is interesting to note that qualitative assessment of site of

thrombotic occlusion in these individuals at necropsy has failed to disclose

evidence of plaque rupture, plaque fissure, or plaque hemorrhage (Virmani et

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al. 1988). These findings have been observed routinely in noncocaine-related

thrombotic coronary arterial occlusion (Davies and Thomas 1984). The

absence of these features in cocaine-related infarction suggests cocaineinduced spasm rather than plaque rupture as a contributing event in the

pathogenesis of infarction in cocaine users.

A second pathologic finding that has been cited to support the role of spasm in

cocaine-related infarction is increased foci of contraction band necrosis in cases

of cocaine-related deaths studied at necropsy (Tazelaar et al. 1987). This

finding also is consistent with the concept that myocardial damage resulting

from cocaine abuse may represent the consequence of cocaine-induced

catecholamine excess, since contraction bands previously have been observed

in association with pheochromocytoma and exogenous catecholamine

administration.

EXPERIMENTAL OBSERVATIONS

The results of experiments performed in vitro and in vivo in live animals and in

vivo in human subjects lend support to the concept that cocaine may act

independently to produce vasownstriction of vascular smooth muscle. In vitro

experiments performed in our laboratory have shown that cocaine alone, in

concentrations of 10-8 to 10-3 M, produces reproducible, reversible

vasoconstriction of aortic rings freshly harvested from normal New Zealand

white rabbits (Rongione and Isner 1989). In these experiments, the magnitude

and direction of vasomotor response to cocaine for those specimens in which

the endothelium had been purposely disrupted were similar to those in which

the endotheiium had been shown pharmacologically to be preserved.

Pretreatment with prazosin or phentolamine produced no consistent effect on

cocaine-induced contraction, whereas pretreatment with diltiazem markedly

inhibited cocaine-induced contraction. These preliminary results suggested that

the vasoconstrictor effect of cocaine on vascular smooth muscle was calciumdependent and endothelium-independent.

Similar findings have been reproduced in ring segments of human arteries,

including coronary arteries, freshly harvested at the time of cardiac

transplantation, and umbilical arteries obtained fresh at the time of cesarean

delivery. In nonatherosclerotic and atherosclerotic human coronary arteries,

vasoconstriction was observed in response to concentrations of cocaine

ranging from 10-9 to 10-3 M (Chokshi et al. 1990). The onset of contraction

appeared after a delay varying from 10 seconds to 6 minutes and increased

until it reached a plateau within 30 minutes. The magnitude of vasownstriction

induced in coronary arterial segments narrowed greater than 50 percent in

cross-sectional area by atherosclerotic plaque was significantly less than that

124
observed in rings narrowed less than 50 percent at all concentrations of

cocaine. In addition to quantitative differences, two qualitative features were

typical of coronary arterial segments narrowed greater than 50 percent in crosssectional area following exposure to cocaine: The rate of rise in tension was

slower, and the time required to reach plateau was prolonged.

The response of human umbilical artery segments exposed to cocaine was

similar to that observed for nonatherosclerotic human coronary arteries (Isner

and Chokshi 1989). The finding that cocaine alone (i.e., without pharmacologic

pretreatment) augments tension in human umbilical arterial segments is

intriguing, since human umbilical artery segments are devoid of sympathetic

innervation. Correspondingly, pretreatment with the alpha-blockers

phentolamine and prazosin had no consistent effect on cocaine-induced

vasoconstriction in these preparations, whereas pretreatment with the calcium

channel blocker diltiazem markedly inhibited cocaine-induced vasoconstriction.

These findings thus contradict the traditional concept that the effects of cocaine

on vascular smooth muscle are the sole result of potentiating the response to

endogenous catecholamines.

Although the above in vitro experiments confirmed the vasownstricting effect of

cocaine alone on medium-size arteries, direct evidence for cocaine-induced

vasoconstriction at the arteriolar level has been reported by Vitullo and

colleagues (1989) using isolated rat hearts perfused with cocaine.

Ultrastructural examination disclosed preserved endothelial integrity in the

constricted arterioles. Morphologic evidence of constriction was supported by

data obtained from Langendorff-heart preparations in which cocaine reduced

myocardial flow rate under conditions of constant pressure. Consistent with the

in vitro work cited above, spasm induced by cocaine was prevented by

pretreatment with calcium channel blockers but not with alpha-adrenergic

antagonists (Stenberg et al. 1989).

Preliminary reports of live animal experiments indicate that certain of these in

vitro observations may be reproduced in vivo. Kuhn and coworkers (1989), for

example, documented dose-dependent vasoconstriction of the left anterior

descending coronary artery in anesthetized dogs given incremental doses of

cocaine. Studies performed in our laboratory have demonstrated that intraarterial administration of cocaine to microswine with experimentally induced

nonocclusive atherosclerotic lesions (Shimokawa et al. 1983) produced intense

vasoconstriction (Isner and Chokshi 1989). Such findings constitute further

inferential evidence that the mechanism of cocaine-induced vasownstriction is

alpha-adrenergic-independent, since provocation of spasm in this model is

accomplished routinely with histamine but does not occur following

administration of norepinephrine. Similar findings have been reported by

125
Egashira and colleagues (1990) in miniswine coronary arteries following

administration of bolus intravenous cocaine (1-10 mg/kg). At 10 mg/kg,

coronary arterial diameter decreased by nearly 40 percent, and coronary flow

velocity decreased by 32 percent, despite a 60-percent increase in the ratepressure product. In this model, pretreatment with prazosin (0.1 mg/kg)

produced attenuation of the cocaine-induced coronary vasoconstriction.

Studies of human subjects performed noninvasively also support the hypothesis

that cocaine may alter coronary reactivity. Nademanee and coworkers (1989)

performed ambulatory electrocardiographic monitoring of 21 male cocaine users

soon after admission to a 28-day substance abuse treatment program. Eight of

the 21 patients with cocaine addiction had frequent episodes of ST elevation

during Holter monitoring; these episodes occurred almost exclusively during the

first 2 weeks of withdrawal. Of the 20 cocaine patients who underwent exercise

treadmill testing, only 1 had a positive test for ischemia.

Perhaps the most intriguing evidence for cocaine-induced vasoconstriction

consists of observations that have been made directly in human patients at the

time of coronary arteriography. Angiographic evidence of spasm in the

coronary artery subtending the site of cocaine-related acute myocardial

infarction has been documented in at least two previous case reports

(Zimmerman et al. 1987; Ascher et al. 1988). In at least eight other patients, an

ergonovine provocative study was performed at the time of diagnostic

arteriography and was interpreted to be negative in all eight cases, implying that

an Inherent predisposition to spontaneous attacks of coronary artery spasm is

neither a characteristic of nor a prerequisite for cocaine-related infarction.

More recently, Lange and colleagues have quantified the degree of

vasoconstriction observed in human epicardial coronary arteries at the time of

diagnostic cardiac catheterization (Lange et al. 1989). Among 45 subjects

undergoing routine coronary arteriography, 2 mg/kg of 10 percent cocaine

hydrochloride administered intranasally produced an 8- to 12-percent reduction

in angiographic luminal diameter of the left coronary artery. Correspondingly,

coronary sinus blood flow fell by 17 percent, while calculated coronary vascular

resistance increased by nearly one-third. These alterations were observed

despite an increase in myocardial oxygen demand, as evidenced by an

increase in the rate-pressure product. Although the magnitude of epicardial

vasoconstrlction observed was mild and diffuse, it is conceivable that larger

doses of cocaine, particularly in individuals with a history of a cocaine-induced

ischemic event, might have induced a more dramatic response. Because the

observed reduction in extramural coronary artery diameter was modest, Lange

and colleagues attributed the increased resistance to vasoconstriction of the

intramural coronary vessels. Phentolamine, an alpha-adrenergic blocker, was

128
found to obviate the vasoactive effects of cocaine, in contrast to the in vitro and

in vivo animal data cited above.

Although the data cited above are consistent with the hypothesis of cocaineinduced spasm, the possibility persists that cocaine-induced myocardial

infarction is multifactorial. Cocaine has been shown in vitro to enhance the

response of platelets to arachidonic acid, leading to increased thromboxane

production and platelet aggregation (Togna et al. 1985). The possibility of

cocaine-induced procoagulant effects recently was suggested Clinically by the

finding of combined protein C and antithrombln III depletion in an individual with

cocaine-related arterial thromboses (Chokshi et al., submitted for publication).

Following discontinuation of cocaine use, the thromboses resolved and levels of

anticoagulants returned to normal. Similarly, Lisse and colleagues (1989) have

reported a high prevalence of upper-extremity, deep venous thrombosis (PagetSchroetter syndrome) among cocaine users. While superficial thrombophlebitis

is a recognized consequence of intravenous cocaine abuse, deep venous

thrombosis is not; the apparent association suggests that the role of cocaine

may be thrombotic in nature. Thus, in situ thrombosis resulting from cocaineinduced procoagulant effects might represent an alternative basis for acute

infarction In patients with previously normal coronary arteries.

SUMMARY

Clinical and experimental data published to date suggest several possible

mechanisms by which cocaine may result in acute myocardial infarction. In

individuals with preexisting, high-grade coronary arterial narrowing, acute

myocardial infarction may result from an increase in myocardial oxygen demand

associated with cocaine-induced increase in rate-pressure product. In other

individuals with no underlying atherosclerotic obstruction, coronary occlusion

may be due to spasm, thrombus, or both. With regard to spasm, the clinical

findings are largely circumstantial, and the locus of cocaine-induced

vasoconstriction remains speculative. Although certain clinical and

experimental findings support the hypothesis that spasm involves the epicardial,

medium-size vessels, other data suggest intramural vasoconstriction. Diffuse

intramural vasoconstriction is not consistent with reports of segmental, discrete

infarction. Whereas certain in vivo data suggest that these effects are alphamediated, other in vitro data suggest the opposite. The finding of cocaineinduced vasoconstriction in segments of (noninnervated) human umbilical artery

suggests that the presence or absence of intact innervation is not sufficient to

explain the discrepant data involving the possibility of alpha-mediated effects.

Finally, the contribution of a primary, thrombotic effect of cocaine has not been

excluded.

127
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cocaine-associated acute myocardial infarction. Am J Cardiol 61:939-941,

1988.

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arteries obtained from freshly explanted human hearts. (Abstract.) J Am

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Chokshi, S.K.; Greene, D.; Sanders, J.; Yao, R.; and Meyers, S. Systemic

vascular thromboemboiism associated with chronic cocaine abuse. Am J

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ACKNOWLEDGMENTS

This work was supported in part by grant HL-40518 from the National Heart,

Lung, and Blood Institute and the Women’s Aid for Heart Research and was

performed during Dr. Chokshi’s tenure as a fellow of the American Heart

Association Massachusetts Affiliate, Needham, MA.

AUTHOR

Jeffrey M. Isner, M.D.

Professor of Medicine and Pathology

St. Elizabeth’s Hospital

Tufts University School of Medicine

738 Cambridge Street

Boston, MA 02135

Saurabh K. Chokshi, M.D.

Practicing Cardiologist

Brandon Cardiology Clinic

320 Oakville Drive

Brandon, FL 33511

130
Cardiac Electrophysiological Effects of

Cocaine in Animal Models

Peter N. Temesy-Arnos, Theodore D. Fraker, Jr., and

R. Douglas Wilkerson

INTRODUCTION

The pathophysiological mechanism for cocaine-related death is uncertain. A

few clinical case reports that associate specific cardiac arrhythmias with

cocaine abuse include asystole (Nanji and Filipenko 1984), accelerated

idioventricular rhythm (Benchimol et al. 1978; Jonsson et al. 1983), a wide

complex tachycardia at 136 beats per minute (Isner et al. 1986), nonsustained

ventricular tachycardia in the setting of acute myocardial infarction (Isner et al.

1986), supraventricular tachycardia (Boag and Havard 1985), and reciprocating

tachycardia in the setting of the Wolff-Parkinson-White syndrome (Chokshi et al.

1989). Of these, only the patient with asystole did not survive. Therefore,

although it is assumed that cardiac arrhythmia is often the immediate cause of

cocaine-related sudden death, both the type and the mechanism of possible

arrhythmias remain unknown.

The purpose of this chapter therefore is to examine the known cocaine-related

arrythmias and cardiac electrophysiological responses in animal models and to

review possible theoretical mechanisms for lethal arrythmias.

DIRECT ACTIONS OF COCAINE ON CELLULAR ELECTROPHYSIOLOGY

In vitro studies of the direct action of cocaine on cellular electrophysiology were

performed by Weidmann (1955), who examined the actions of cocaine on calf

and sheep Purkinje fibers. He observed a reduced resting membrane potential

and a decrease of amplitude and a decrease in the fast upstroke of the action

potential with cocaine. These results are associated with decreased

conduction. Weidmann also observed that spontaneous activity of the action

potential ceased. Recently, Przywara and Dambach (1989) extended these

observations in rabbit atrial and ventricular tissues. These investigators also

demonstrated that cocaine depressed the fast upstroke of action potentials, An

increase in action potential duration and in the effective refractory period of

131
atrial and ventricular tissues also was observed; however, the effect was more

profound in atrial tissues, Przywara and Dambach also demonstrated a

decrease in sinus rate. They concluded that direct cocaine effects are

characteristic of the actions of Class I (local anesthetic) antiarrhythmic agents.

IN VIVO ELECTROPHYSIOLOGICAL EFFECTS OF COCAINE

Most of the current information regarding in vivo electrophysiological effects of

cocaine to date comes from brief, preliminary reports, which are summarized in

table 1. Although cocaine’s effect on heart rate differs in various studies, these

variations may be explained by the dose of cocaine used, the brief duration of

action, and the presence or absence of anesthesia. Our results indicate that

cocaine has a brief, dose-dependent increase of heart rate in the conscious

animal (Temesy-Armos et al. 1989a). Slowing of conduction velocity in the

ventricle and the atrium has been demonstrated by us and several other

researchers (Schwartz et al. 1989a; Kanter et al. 1988; Temesy-Armos et al.

1989a). Kabas and colleagues (1989) demonstrated slowing of conduction

velocity in the His-Purkinje system at 3 and 5 mg/kg while Tracy and coworkers

(1989), using a lower dose of cocaine (2mg/kg), observed slowing of conduction

velocity in the atrioventricular (AV) node and in the His-Purkinje system only

after both limbs of the autonomic nervous system were pharmacologically

blocked by propranolol and propantheline. We also have demonstrated

cocaine-induced increase in the atrial effective refractory period (TemesyArmos et al. 1989a). However, cocaine’s effect on the ventricular effective

refractory period differs in several studies as shown in table 1 (Schwartz et al.

1989b; Kanter et al. 1988; Tracy et al. 1989; Temesy-Armos et al. 1989a).

The above results suggest that cocaine has dose-dependent effects that can be

explained either by cocaine’s known action to augment sympathetic tone

(Ritchie and Greene 1990) or by cocaine’s Class I antiarrhythmic action, The

effect on heart rate can be explained best by an augmentation in sympathetic

tone, whereas the effects on conduction velocity and the atrial effective

refractory period are most likely due to cocaine’s local anesthetic effects. The

variable effects on the ventricular effective refractory period may be due to the

opposing actions of augmenting sympathetic tone and local anesthetic activity.

Sympathetic input, which tends to shorten the effective refractory period, has a

greater effect on the ventricle than on the atrium (Wit et al. 1975). Cocaine

causes less lengthening of the effective refractory period in the ventricle than in

the atrium (Przywara and Dambach 1989). Thus, the variable results of cocaine

on the ventricular effective refractory period may be explained by the relative

input of these opposing actions.

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TABLE 1. Preliminary reports on in vivo electrophysiological effects of cocaine
COCAINE-INDUCED ARRHYTHMIAS IN ANIMAL MODELS

Two studies suggest that an extremely large dose of cocaine can produce

arrhythmias within a few minutes after cocaine infusion. In a preliminary report,

Kanter and colleagues (1988), using a 10 or 15 mg/kg intravenous (IV) bolus of

cocaine followed by an infusion of 0.096 or 0.114 mg/kg/min in anesthetized

dogs, reported ventricular tachycardia in 5 of 19 dogs, AV block in 3 of 19 dogs,

and sinoatrial block in 3 of 19 dogs within 2 minutes of the bolus. Schwartz and

coworkers (1989a) reported a wide complex tachycardia in one anesthetized

dog beginning 10 seconds after an IV cocaine bolus of 8.4 mg/kg was added to

a previous infusion of 13.8 mg/kg. They also reported a slow idioventricular

rhythm within minutes of a cocaine bolus of 37.7 mg/kg added to a previous

infusion of 40 mg/kg in an anesthetized dog.

Lower doses have not been shown to produce such early arrhythmias unless a

concurrent, second intervention is present. Ruben and Morris (1952)

demonstrated that the combination of cocaine and epinephrine could produce

ventricular fibrillation in conscious and unconscious dogs. Billman and Hoskins

(1988) reported that cocaine could produce ventricular fibrillation in conscious

dogs in the setting of acute coronary occlusion and exercise. lnoue and Zipes

(1988) showed that cocaine produced ventricular tachycardia in dogs with acute

myocardial infarction which also received IV norepinephrine.

Our recent study in dogs showed delayed cardiac arrhythmias following

cocaine, recorded on long-term continuous (Holter) electrocardiograms

(Temesy-Armos et al. 1989b). Twelve conscious dogs had 26 hour long

continuous ambulatory electrocardiographic recordings performed prior to

cocaine and after IV cocaine at 4 mg/kg. Of the 10 dogs that showed no

ventricular tachycardia on the baseline recording, 5 developed ventricular

tachycardia after cocaine, which appeared 5.7±4.6 hours after cocaine

administration. Two of these 5 dogs developed lethal arrhythmias: One of

them was a ventricular tachycardia at 300 beats per minute progressing to

ventricular fibrillation and the other was sinus bradycardia progressing to

asystole.

POSSIBLE MECHANISMS OF COCAINE-INDUCED LETHAL

ARRHYTHMIAS

Cocaine-associated sudden death may be due to multiple arrhythmias including

asystole and ventricular fibrillation. Some preliminary reports suggest that there

may be several phases after cocaine when lethal arrhythmias may appear:

“early” arrhythmias related to large doses and, much later, arrhythmias that may

occur with lesser doses. At present, the mechanism of cocaine-related

arrhythmias is uncertain. Based on electrophysiological observations,

134
the following theoretical mechanisms seem plausible. Asystole may be due to

cocaine’s Class I antiarrhythmic effect, which results in decreased automaticity

and a slowing of conduction velocity. This local anesthetic effect of cocaine

also may result in a profound negative inotropic effect (Fraker et al. 1990),

which could lead to cardiac arrest. Other theoretical mechanisms for decreased

automaticity and conduction include an increase in parasympathetic tone

mediated by ischemia to the inferoposterior left ventricle (Thames et al. 1978)

and a cocaine-mediated hypertension response (Wilkerson 1988; Flschman et

al. 1976; Javaid et al, 1978; Foltin et al. 1988).

Ventricular tachyarrhythmias may be due to reentry, abnormal Impulse initiation,

or both. Reentry may be mediated by Increased sympathetic tone or Type I

antiarrhythmic activity (Han and Moe 1964; Rosen and Wit 1987). Abnormal

impulse initiation, including triggered automaticity, also may be mediated by

increased sympathetic tone (Wit et al. 1975) or by agents with Type I

antiarrhythmic activity (Rosen and Wit 1987). In addition, a change in

myocardial substrate, such as ischemia (Han and Moe 1964; Wellens 1975) or

myocarditis (Vignola et al. 1984), could predispose to reentry and ventricular

tachyarrhythmias.

CONCLUSIONS

The electrophysiological responses to cocaine as observed in animal models

can be explained by cocaine’s opposing actions of increasing sympathetic tone

and its Type I antiarrhythmlc activity. Preliminary reports of animal models

suggest that cocaine-related sudden death may be due to multlple arrhythmias,

including asystole and ventricular fibrillation. The mechanism for such lethal

arrhythmias is uncertain; however, they may be due to a cocaine-mediated (1)

increase in sympathetic tone, (2) Type I antiarrhythmic activity, (3) change In

myocardial substrate, or (4) a combination of these cocaine actions.

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high-dose intravenous cocaine in dogs. J Am Coll Cardiol 13:60A, 1988.

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ACKNOWLEDGMENT

This work was supported by National Institute on Drug Abuse contract

271-87-8130.

AUTHORS

Peter N. Temesy-Armos, M.D.

Associate Professor of Medicine

137
Theodore D. Fraker, Jr., M.D.

Associate Professor of Medicine

Division of Cardiology

Department of Medicine

Ft. Douglas Wilkerson, Ph.D.

Professor of Pharmacology

Department of Pharmacology

Medical College of Ohio

P.O. Box 10008

Toledo, OH 43699-0008

138
Effects of Cocaine on Intracellular

Calcium Handling In Cardiac and

Vascular Smooth Muscle

Cynthia L. Perreault, Kathleen G. Morgan, and James P. Morgan

INTRODUCTION

The purpose of these studies was to test the hypothesis that the major effect of

the cardiovascular toxicity of cocaine is due to drug-Induced alterations in

intracellular calcium ([Ca2+]1) handling. This hypothesis is reasonable because

calcium is an important second messenger for excitation-contraction coupling of

both the heart and blood vessels (Ruegg 1988; Morgan and Morgan 1984a).

Excitation-contraction coupling in any muscle type can be outlined by the

process shown in figure 1. Ca2+ can enter the cytoplasm from either the

extracellular fluid or intracellular stores. Entry of Ca2+ from the extracellular fluid

is thought to play a larger role with respect to individual contractions in smooth

muscle than in cardiac muscle. In cardiac and smooth muscle, Ca2+ can enter

the cell via a calcium-mediated action potential; in vascular smooth muscle,

receptor-operated channels that are associated with little or no change in

membrane potential also play a role. Ca2+ is thought to be extruded from the

cell either by adenosine triphosphate (ATP)-dependent calcium pumps or by the

Na+-Ca2+ exchanger. An increase in [Ca2+], acts on the regulatory proteins to

cause contraction of the myofilaments. In cardiac muscle, the regulatory

proteins (the troponin complex) serve to restrain the actin and myosin

molecules from their natural tendencies to form cross-bridges and to split ATP;

the function of Ca2+ is to remove this inhibition, When [Ca2+],declines to resting

levels, inhibition is restored and the muscle relaxes. In smooth muscle, the

situation appears to be quite different. When isolated and purified, smooth

muscle actin and myosin have little tendency to form cross-bridges or to split

ATP-they are in an inactive state. The function of the smooth muscle

regulatory proteins appears to be to activate the myofilaments, and the function

of Ca2+ is to turn on this activation process. This occurs via calcium-mediated

activation of the enzyme, myosin light chain kinase, which in turn mediates the

phosphorylation of the light chains of myosin (shown as pathway of force

development in figure 2). The phosphorylated form of myosin is active and

139
can then combine with actin to split ATP and undergo cross-bridge cycling.

Whether Ca2+ must be present during the cycling of cross-bridges of

phosphorylated myosin remains controversial. However, it is clear that Ca2+ is

essential for initiating the contraction of cardiac and vascular smooth muscle

under most conditions.

FIGURE 1. Simplified scheme of excitation-contraction coupling in cardiac

and vascular smooth muscle

SOURCE: Morgan and Morgan 1984a, copyright 1984, American Journal of

Medicine.

There also appears to be a second mechanism for altering the contractile state

of cardiac and vascular smooth muscle that is independent of changes in [Ca2+],

(Endoh and Blinks 1988; Morgan et al. 1988; Bradley and Morgan 1987).

Under the influence of some drugs and during certain pathophysiologic states,

the Ca2+-force relationship can be altered so that a given level of [Ca2+],

produces less or greater force per unit of cross-sectional area than would be

expected under control conditions. This change reflects an alteration in the

140
FIGURE 2. Mechanisms of force development and maintenance in vascular

smooth muscle

SOURCE: Morgan et al. 1988, copyright 1988, New York Academy of

Sciences,

myofilament Ca2+ responsiveness. Such a change can be produced in cardiac

muscle by drugs such as caffeine or sulmazole which increase myofilament

Ca2+ sensitivity, and by hypoxia, ischemia, and catecholamines, which decrease

myofilament Ca2+ responsiveness, In vascular smooth muscle, dramatic

increases in Ca2+ responsiveness can be produced by certain phorbol esters

(Jiang and Morgan 1987, 1989) and by prostaglandin F2a, which may activate

the protein kinase-C pathway (shown as pathway of force maintenance in figure

2).

On the basis of the information presented above, the cellular mechanism of any

drug which affects the inotropic state of cardiac muscle or the tone of vascular

smooth muscle must be considered in terms of its actions on (1) intracellular

Ca2+ levels and (2) myofilament Ca2+ responsiveness. The effects of cocaine on

these two mechanisms were evaluated in mammalian cardiac and vascular

tissues, as described below.

141
METHODS

Cardiac Muscle Experiments

Left and right atrial strips were excised from the hearts of adult male ferrets

under chloroform anesthesia. The methods of preparation and instrumentation

used in these studies have been described elsewhere in detail (Morgan et al.

1988; Bradley and Morgan 1987; Jiang and Morgan 1987, 1989; Blinks 1966;

Kihara and Morgan 1989; MacKinnon et al. 1988). After removal from the

hearts, muscles were maintained in a physiologic salt solution at 30°C and

stimulated to contract at 3-second intervals with pulses of 5 msec duration.

Unless otherwise specified, threshold voltage (i.e., 10 percent above threshold

voltage, which typically is about 1 volt) was used to stimulate the muscles;

under some circumstances, suprathreshold field stimulation was used to

maximize catecholamine release from the adrenergic nerve endings (Blinks

1966). An initial P-hour equilibration period was allowed during which muscles

were gradually stretched to the length where maximal isometric force

developed. In one group of muscles, cumulative concentration-response

relationships for norepinephrine and calcium were determined in the presence

of 10-5 M cocaine. In a second group of muscles, the bioluminescent protein

aequorin was loaded by a chemical approach described in detail elsewhere

(Kihara and Morgan 1989; MacKinnon et al. 1988). Light signals were recorded

with a photomultiplier by means of a light-collecting apparatus with the design

described by Blinks (1982). A third group of muscles was subjected to

increasing frequencies of field pulses before and after the addition of 10-5 M

cocaine to the bathing medium.

Vascular Smooth Muscle Preparations

Left anterior descending coronary artery segments were removed from the

hearts of swine that had been anesthetized with pentobarbitai before cardiac

excision and placed in an organ bath containing physiologic salt solution at

37.5°C as described previously (Bradley and Morgan 1987; Morgan and Morgan

1984b, 1984c). In each smooth muscle experiment, the strip was stretched to

the length at which maximal isometric tension developed as indicated by the

contractile response to depolarization with 60 mM KCI. The luminal surface of

each segment was rubbed with a rubber policeman to remove the endothelium.

Lack of a functional endothelium in these preparations was indicated by a

constrictor response to carbachol. Segments then were loaded with aequorin,

the bioluminescent Ca2+ indicator, by a previously described method (Morgan et

al. 1988; Bradley and Morgan 1987; Jiang and Morgan 1987, 1989).

142
Drugs and Chemicals

It is possible for drugs to interact directly with aequorin and modify the

luminescent reaction or the sensitivity of aequorin to Ca2+. Therefore, the

potential for interaction of cocaine and aequorin was tested in vitro using the

basic method and calibration device described by Endoh and Blinks (1988).

After initiating the aequorin luminescence reaction with Ca2+, in vitro cocaine

was added to the reaction pipette; the drug had no effect on the luminescence

reaction until concentrations in excess of 10-4 M were achieved. In these

concentrations, the combination of cocaine plus aequorin appeared to decrease

the light emission.

Peak tension, peak light, and relaxation times were compared by Student’s ttest and multiple sample comparison tests; statistical significance was set at

p<0.05.

RESULTS

Cardiac Muscle Experlments

Figures 3, 4, and 5 show the actions of cocaine on ferret atrial strip

preparations. Atropine, 2x10-6 M, was present in the bathing medium during all

experiments to block the effects of acetylcholine released from the

parasympathetic nerve endings. Figure 3 shows that 10-5 M cocaine produced

a positive inotropic effect in [Ca2+]o

 up to 4 mM; this effect was blunted at higher

[Ca2+], where the muscles approached maximal activation. Figures 4 and 5

show that 10-5 M cocaine produced a leftward shift in the dose-response

relationship of norepinephrine, whether applied exogenously into the bathing

medium (figure 4) or released by suprathreshold field stimulation (figure 5).

Figure 6 shows the effects of 10-5 M cocaine on an aequorin-loaded ferret atrial

strip. The cocaine produced a marked positive inotropic effect that was

associated with an increase in [Ca2+]1

. This effect could be exacerbated by

using field vs. punctate stimulation to enhance the release of norepinephrine

from the adrenergic nerve endings; it could be ameliorated by the addition of

propranolol. Higher concentrations of cocaine (i.e., >10-5 M) produced a doserelated negative inotropic effect in this atrial preparation that was associated

with a corresponding decline in [Ca2+]1

.

143
FIGURE 3. Effects of cocaine, 10-5 M, on the calcium concentration response

curve of ferret atrial muscle (30°C; 3 Hz; atropine, 2x10-5 M, in

bath)

NOTE: Values=mean±SEM

*p<0.05

144
FIGURE 4. Effects of cocaine, 10-5 M, on the norepinephrine concentration

response curve of ferret atria/ muscle (30°C; 3 Hz; atropine,

2x10-6 M, in bath). Responses have been normalized by

maximum response to calcium.

NOTE: Values=mean±SEM

*p<0.05

145
FIGURE 5. Effects of cocaine, 10-5 M, on the response to field stimulation

(30°C; 3 Hz; atropine, 2X10-6 M, in bath)

NOTE: Values=mean±SEM

*p<0.05

Solid line and open circles=control

Dashed line and solid circle=10-5 M cocaine

146
FIGURE 6. Effects of cocaine, 10-5 M, on isometric tension and [Ca2+], in a

ferret atrial strip. Upper trace, light (i.e., [Ca2+]1 recorded with

aequorin in nanoAmperes (nA); middle trace, isometric tension in

milligrams (mg); lower trace, stimulus artifact. Temperature=3O°C;

3 Hz punctate stimulation; atropine, 2x10-6 M, in bath.

Vascular Smooth Muscle Studies

Figure 7 shows that cocaine and EGTA produced relaxation of a porcine

coronary artery segment contracted with 60 mM KCI. The relaxation occurring

in response to EGTA was associated with a marked decline in [Ca2+]1. In

contrast, the relaxation in response to cocaine was accompanied by little

change in the intracellular Ca2+ levels, suggesting that the drug was producing

vasorelaxation through a Ca2+-independent mechanism.

DISCUSSION

Cardiac Effects of Cocaine on Amplitude of Intracellular Calcium

Transient and lsometric Contraction

As shown in figure 6 for a ferret atrial muscle, the aequorin light signal (i.e., [Ca2+]1

transient) from mammalian working myocardium consists of a single component

that temporally precedes the corresponding tension response. These findings are

consistent with current models of excitation-contraction coupling that predict that

mechanical contractile events are preceded by changes in intracellular calcium

concentrations (Ruegg 1988; Morgan and Morgan 1984a). Interpretation of the

aequorin light signals has been detailed elsewhere (Morgan and Morgan 1984a,

1984b, 1984c; MacKinnon et al. 1988). Cocaine produces a positive inotropic

effect in ferret atrial muscle under conditions in which catecholamine release from

the adrenergic nerve endings is maximized (Perreault et al. 1988). This occurs

due to cocaine-mediated blockade of adrenergic reuptake of norepinephrine

147
FIGURE 7. Effects of cocaine, 10-3 M (panel A) and EGTA, 4 mM (panel B)

on tone and [Ca2+]1

 of a swine coronary artery segment stimulated

to contract with 60 mM KCI. Upper panels show aequorin light

signal (i.e., [Ca2+]1

) in nA of anodal current from photomultiplier;

lower panels show isometric force. Note that EGTA-induced

relaxation is associated with a decline in [Ca2+]1

, but cocaineinduced relaxation is not. Note that a wash artifact occurred at

the beginning of the second trace, causing an uncharacteristic

initial spike. Abbreviations are the same as those in figure 6.

(Iverson 1971). In ferret papillary muscles (Hague et al. 1988) concentrations of

cocaine in excess of 10-5 M produce the opposite effect, which probably is related

to the local anesthetic actions of the drug. Local anesthetics characteristically

block sodium influx via the voltage-dependent “fast” sodium channels in the

sarcolemma. Under normal circumstances, intracellular sodium homeostasis is

maintained, in part by a sodium-calcium exchange mechanism located in the

sarcolemma, which transports intracellular sodium ions to the extracellular space

in exchange for extracellular calcium ions. Decreased intracellular sodium

concentrations impair the function of this exchanger so that intracellular calcium

levels fall. It is important to note that the sarcolemmal actions of norepinephrine

tend to antagonize this inhibitory effect of local anesthetics on the voltagedependent sodium channels. In preparations in which the nerve endings are

146
depleted by the presence of disease or reserpine, positive inotropic responses to

cocaine are not observed (Perreault et al. 1989a). Instead, a dose-related

negative inotropic effect can be demonstrated from concentrations as low as

10-6M.

As shown in figure 8, cocaine also abbreviates the light signal and twitch in

concentrations of 10-5 M. This abbreviation may be due in part to catecholamine

release by the adrenergic nerve endings (Morgan and Blinks 1982). However,

in addition, cocaine and other local anesthetic agents may have direct effects

on the cardiac sarcolemma (Josephson and Sperelakis 1976), sarcoplasmic

reticulum (Blinks et al. 1972), and myofilaments (Perreault et al. 1990).

Vascular Effects of Cocaine on lsometric Tone

We have reported previously that cocaine produces relaxation of control and

potassium-contracted coronary artery segments from pigs (Perreault et al.

1989a, 1989b). Moreover, cocaine produces similar vasodilatory responses in

coronary artery segments from humans (Perreault et al. 1989a, 1989b). In

contrast, cocaine produces an intense vasoconstrictor response in arterial

segments from several animal species, including the ferret, that appear to be

mediated by alpha-adrenergic stimulation (Ritchie and Greene 1985; Brown et

al. 1984). Such an effect would not be expected in swine epicardial coronary

artery segments because of their relative insensitivity to alpha-agonists due to a

low density of alpha-adrenergic receptors (Bradley and Morgan 1987). A

minimal response to alpha-adrenergic agonists also appears to be characteristic

of epicardial coronary artery segments from humans (Ginsburg et al. 1980;

Ginsburg 1983), although this responsiveness may be altered in vivo by the

presence of ischemic heart disease (Mudge et al. 1976). Evidence is

accumulating that suggests that the microvessels may contract in response to

cocaine; this effect is ameliorated by alpha-adrenergic blockade (Lange et al.

1989).

Vascular Effects of Cocaine on Coronary Artery Calcium Sensitivity

We have reported previously that calcium-independent mechanisms play a

major role in modulating contraction-relaxation cycles of vascular smooth

muscle (Morgan and Morgan 1984a, 1984c; Morgan et al. 1988). The results

shown in figure 7 suggest that cocaine-mediated vasorelaxation is produced by

such mechanisms because intracellular Ca2+ levels appear to change little in the

face of marked decreases in tonic tension. We have reported similar results in

human coronary artery segments (Perreault et al. 1989a). Calciumindependent changes in vascular tone have been reported for prostaglandins

and phorbol esters (Bradley and Morgan 1987; Jiang and Morgan 1987, 1989).

The vasoconstriction produced by these agents has been interpreted in terms of

149
a change in a calcium-independent second messenger system involving protein

kinase-C. Activation of protein kinase-C may result in phosphorylation of a site

on the thick or thin filaments or the associated regulatory protein, which appears

to alter the Ca2+ sensitivity of the contractile apparatus. This scheme is outlined

in figure 2. Whether such a mechanism plays a role in mediating the Ca2+

-

independent relaxation produced by cocaine remains to be established.

However, relaxation appears to be primarily governed by a Ca2+-independent

mechanism rather than by decreased availability of intracellular calcium, as was

seen in the heart.

SUMMARY AND CONCLUSION

The inotropic and lusitropic (i.e., relaxant) actions of cocaine on the heart

appear to be caused primarily by changes in intracellular calcium handling. The

positive inotropic and lusitropic effects of low and moderate concentrations (i.e.,

<=10-5 M) are mediated by catecholamines; the negative inotropic effects of

higher concentrations appear to be due to the direct local anesthetic effects of

cocaine on excitation-contraction coupling mechanisms. The relevance of

these findings to humans is suggested by the fact that blood levels of cocaine in

excess of 10-5 M have been described in patients abusing this drug (Van Dyke

et al. 1978; Paly et al. 1982). Blood vessels from certain vascular beds,

including the epicardial coronary arteries of humans and swine, show little or no

constrictor response to low concentrations of cocaine and relax at higher

concentrations. In contrast to the effects on the heart, the relaxant effects of

cocaine on vascular smooth muscle appear to be related to marked changes in

myofilament calcium responsiveness, which may be mediated by the protein

kinase-C system. These results at least indicate that the depressant effects of

cocaine on cardiac vs. vascular smooth muscle occur by different mechanisms

and suggest the need for specific therapeutic approaches to managing cardiac

depression vs. vasodilatation when they occur in cocaine-intoxicated

individuals. Moreover, these data provide evidence supporting the hypothesis

that the net effects of cocaine in the intact organism are highly dependent on

the underlying level of sympathetic adrenergic activity.

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ACKNOWLEDGMENTS

This work was supported in part by National Institute on Drug Abuse grant DA05171; a Research Career Development Award to JPM from the National Heart,

Lung, and Blood Institute; and National Institutes of Health grant HL-31704.

152
AUTHORS

Cynthia L. Perreault, B.S.

Research Associate

Harvard-Thorndike Laboratory

Kathleen G. Morgan, Ph.D.

Associate Professor of Physiology in Medicine

Harvard Medical School

James P. Morgan, M.D., Ph.D.

Associate Professor of Medicine

Harvard Medical School

Cardiovascular Division

Beth Israel Hospital

330 Brookline Avenue

Boston, MA 02215

153
Cocaine-Induced Changes in the

Biochemistry and Morphology of

Rabbit Aorta

Ronald O. Langner and Collette L. Bement

INTRODUCTION

The abuse of cocaine has been implicated in a number of cardiovascular

toxicities, including coronary vasospasm and thrombosis, stroke, myocardial

infarction, angina pectoris, arrhythmia, rupture of the aorta, and sudden death

(Isner et al. 1986; Mittleman and Wetli 1987). These effects have been seen in

all age groups with variable doses of cocaine and routes of administration, in

individuals with cardiovascular disease, and in those with normal coronary

artery angiography. The biochemical mechanisms involved in these responses

to cocaine remain unknown.

Several current reports in the literature strongly suggest that cocaine can cause

injury to blood vessels that may eventually precipitate an acute myocardial

accident (Frischman et al. 1989; Simpson and Edwards 1986). Cocaine is

known to interact with the sympathetic nervous system by potentiating the

excitatory and inhibitory responses of sympathetically innervated organs to

epinephrine and norepinephrine (Woods and Downs 1973). The

sympathomimetic action of cocaine seems to be related primarily to its ability to

block neuronal reuptake of norepinephrine.

Several investigators have demonstrated that the administration of

catecholamines can result in both biochemical and histopathological changes

which have many similarities to the early stages of human arteriosclerosis

(Oester 1959; Lorenzen 1981). Langner and Fuller (1973) have demonstrated

that, In the rabbit, one of the earliest catecholamine-induced biochemical

changes in the arterial wall was an increase in the rate of aortic collagen

synthesis, which was observed after only 4 days of treatment and before any

gross alterations in aortic morphology were noted. These authors suggested

that changes in aortic collagen synthetic rates represented a primary

biochemical defect.

154
The catecholamine-induced aortic plaques were seen after 10 or 15 days of

drug treatment and were primarily localized In the ascending and descending

portions of the aortic arch and In the thoracic aorta. Histologically, changes

were seen primarily in the medial layers of the aorta and were characterized by

damage and/or disappearance of the elastic lamellae and an infiltration of the

injured area with fluid, proteins, and glycosaminoglycans. Surrounding this

necrotic area were layers of smooth muscle cells that appeared to be active

both as fibroblasts and phagocytes. Calcification of the Injured area seemed to

be a secondary event that followed the deposition of glycosaminoglycans.

These catecholamine-induced lesions did not exhibit increased lipid

accumulation: however, experimental studies by Constantinides and coworkers

(1958) have shown that arteries injured by catecholamine administration

incorporated lipids when rabbits were fed a high cholesterol diet.

The mechanisms whereby catecholamine caused these changes are unknown.

Waters and de Suto-Nagy (1950) suggested that the hypertensive effect of the

catecholamines caused an injury to the endothelial lining that was responsible

for the observed changes. Based on current theories of atherogenesis (Ross

1986), this injury then could lead to the development of arteriosclerotic lesions.

Numerous theories have been proposed to explain the pathogenesis of

arteriosclerosis. Currently, the most widely accepted theory is the response-toinjury hypothesis. Ross and Glomset (1976) proposed that all atherosclerotic

risk factors, as well as mechanical, chemical, viral, and immunologic agents,

injure the arterial endothelium and cause endothelial injury, which is followed by

platelet adhesion and aggregation at the site of injury, with subsequent release

of platelet-derived growth factor (PDGF). The release of PDGF stimulates

migration and proliferation of smooth muscle cells in the intima and secretion of

connective tissue components. In the presence of repeated damage or irritation

to the endothelium, smooth muscle cells are thought to accumulate large

amounts of cholesterol, resulting in cellular necrosis. This is complicated further

by a buildup of fibrous tissue (mostly collagen) and calcium, leading to a

clinically significant narrowing of the artery.

It has been hypothesized that cocaine-induced myocardial infarction results

from an injury of the coronary artery that leads to increased platelet

aggregation, thrombus, and arterial spasms (Frischman et al. 1989). Although

this hypothesis is interesting, there is no direct evidence that the administration

of cocaine has the potential to directly or indirectly injure blood vessels.

Previous studies in our laboratory (Langner et al. 1988) have reported that

cocaine can cause both histological and biochemical changes in aortic tissue,

which suggests that cocaine has the potential to cause injury to the blood

vessel wall. The purpose of the present studies was to determine the effects of

155
daily vs. alternate-day cocaine administration and to further define the

biochemical and histological changes that occur following each pattern of

cocaine administration.

METHODS

Adult male New Zealand rabbits weighing between 2.5 and 3.0 kg were used in

this study. The animals were housed routinely in a room with a constant

temperature (25°C) and a 12-hour light/dark cycle. Commercial rabbit chow and

water were given ad libitum. For the daily cocaine treatment study, 25 rabbits

were divided into two groups. Seven rabbits were placed in the saline control

group; and 18 rabbits were placed in the cocaine treatment group. Each rabbit

was weighed daily and injected via the marginal ear vein for 14 days using an

infusion pump set to deliver fluid at a rate of 1 mL/min. The control animals

were injected with sterile 0.9 percent saline for 1 minute. The cocaine-treated

rabbits were injected with a 15 mg/mL solution of cocaine in 0.9 percent sterile

saline at a concentration of 5 mg/kg. The dose of 5 mg/kg was selected

because the authors’ previous studies had demonstrated that this dose of

cocaine would visibly stress the animals without causing excessive mortality.

For the alternate-day dosing study, 16 rabbits were divided into two groups. Six

rabbits were placed in the saline control group, and 10 rabbits were placed in

the cocaine treatment group and received cocaine injections at a dose of 5 mg/

kg every other day for a total of 14 injections over 28 days. The animals in the

alternate-day treatment group received the same total amount of cocaine as the

daily cocaine-injected rabbits, but it was given over a longer period.

Twenty-four hours after the last injection, blood was drawn from the medial ear

artery for determination of serum cholesterol, and the rabbits were killed. The

thoracic cavity was opened, and the thoracic aorta from the beginning of the

ascending aortic arch to the level of the celiac artery was quickly removed. The

aorta was cleaned of loosely adhering tissue, opened longitudinally, and

inspected for gross aortic plaques. A small section of the thoracic aorta located

at the base of the aortic arch then was excised immediately, weighed, and

frozen in liquid nitrogen. The sample was stored at -70°C until analysis for

cyclic adenosine monophosphate (AMP) content. A second aortic section was

taken from this region for histological evaluation. The tissue section was fixed

in buffered formalin and stained with hematoxylin and eosin or Verhoeff’s stain

for elastin. The remaining tissue was minced into smaller pieces, placed in

Krebs’ bicarbonate buffer (pH 7.4) and preincubated for 20 minutes, The aortic

minces were then placed in fresh Krebs’ buffer containing 3 mCi of 14C-proline

and 0.2 mM L-proiine and incubated for 90 minutes following previously

reported procedures (Langner and Bement 1985).

156
Following the incubation period, the tissue samples were rinsed with ice-cold 5

percent trichloroacetic acid (TCA) to prevent further incorporation of the labeled

proline. The tissues were homogenized in nine volumes of normal saline using

a glass, motor-driven, coaxial homogenizer. The synthetic rates of collagen and

noncollagen proteins were estimated by the hot TCA-extraction procedure

described by Newman and Langner (1975). Briefly, the procedure was as

follows: An aliquot of homogenate was washed with ice-cold 5 percent TCA to

remove any unincorporated 14C-proiine and was centrifuged. The resulting

pellets were extracted twice with 5 percent TCA at 90°C for 60 minutes. The

TCA extracts were evaporated to dryness, resolubilized in distilled water, and

counted in a liquid scintillation counter. These samples were used as an

estimate of collagen synthetic activity. The pellet remaining after the extraction

of collagen was digested overnight and then was counted in a liquid scintillation

counter. These samples were used as an estimate of noncollagen protein

synthetic activity.

The hydroxyproline content of the aortic homogenate was estimated by the

method of Kivirikko and colleagues (1967) and was used as an index of tissue

collagen content. Noncollagen protein concentrations were determined on the

tissue homogenate using the method described by Lowry and colleagues

(1951), with bovine serum albumin as the standard. The cholesterol content of

each tissue was determined after lipid extraction following the procedures

outlined by Omodeo and coworkers (1984) and Carlson and Goidfarb (1977).

The calcium content of each aorta was estimated following the procedures

described by Watts and coworkers (1987). The cyclic AMP content of the aorta

was determined using a commercially available radioimmune assay kit. Serum

cholesterol levels were determined on the ethanoiic extract of blood collected

from the medial ear artery following the method described by Franey and

Amador (1968). The data were compared for differences between means of

groups by a one-way analysis of variance, When statistically significant

differences were indicated, Duncan’s multiple-range test was used for multiple

comparisons between groups with unequal means at a level of significance of

p<0.05 (Snedecor and Cochran 1976).

RESULTS AND DISCUSSION

The purpose of these studies was to test the hypothesis that the abuse of

cocaine has the potential to cause serious injury to blood vessels. In these

studies, rabbits were injected intravenously with cocaine at a dose of 5 mg/kg.

This dose of cocaine, which is approximately one-third the reported LD50 for

the intravenous (IV) administration of cocaine to rabbits (Rose et al. 1930),

visibly stressed the rabbits but did not result in excessive deaths. The dose

also is well within the dose range seen in humans since recent reports cite

157
doses of 0.5 to 1 g of cocaine as being administered before incidences of

cardiac toxicity (Isner et al. 1986; Wang et al. 1988). Of the rabbits given daily

injections of cocaine, one rabbit died after its 13th injection, and a second rabbit

died after its 14th injection. Of the rabbits injected with cocaine on alternate

days, one rabbit died immediately after its 6th injection, and a second rabbit

died following its 10th injection. The exact cause of death in these rabbits was

not determined, but it was presumably due to cardiac and/or respiratory

depression, A third rabbit in this group broke its back as a result of a strong

contraction that occurred after its flrst cocaine injection and had to be killed.

Several studies have demonstrated that elevation of aortic protein synthetic

rates is an early and reliable indicator of aortic injury. The data in table 1 clearly

demonstrate that the administration of cocaine on either a daily or an alternateday basis resulted in elevated rates of total protein synthetic rates in some of

the rabbits, which were defined as responder rabbits. To be classified as a

responder, a rabbit had to have a total aortic protein synthetic activity that was

at least two standard deviations above the mean aortic protein synthetic rate of

the control group. As shown in table 1, 8 of the 14 daily-injected rabbits were

classified as responder rabbits, and 4 of the 7 alternate-day injected rabbits

were classified as responders. The remaining rabbits in each group were

classified as nonresponders. This classification of responders and

nonresponders was maintained in all subsequent tables. The mechanism by

TABLE 1. Aortic protein synthesis in rabbits given either daily or alternateday IV injections of cocaine

Group

Total Collagen Noncollagen

N (DPM/TH) (DPM/TH) (DPM/TH)

Dally Injections

Control 7 21,356±2,962 7,622±1,197 13,7331±1,808

Cocaine

Responder 6 49,002±4,565a

17,356±2,193 31,645±2,666

Nonresponder 6 18,557±1,276 6,604±5,488 12,463±8,064

Alternate-Day lnjections

Control 6 18,308±1,226 5,464±458 12,842±830

Cocaine

Responder 4 27,696±516 8,583±661 19,113±670

Nonresponder 3 17,810±337 4,771±344 13,038±295

NOTE: All results are presented as mean±SE; TH=thoracic aorta.

a

p<0.05 when compared with control group

158
which cocaine-induced aortic collagen and noncollagen protein synthetic rates

in the responder group of rabbits, but not in the nonresponder group, is

unknown. Because the New Zealand rabbit is not a genetically homogenous

breed, it is possible that inherent genetic differences are responsible for the

observed results. Additional studies are needed to clarify this issue.

As shown in table 2, there are no significant differences in the amount of aortic

collagen or noncollagen protein content in either the responder or the

nonresponder rabbits. Total aortic collagen content was estimated by

measuring the amount of aortic hydroxyproline. This amino acid is found

primarily in collagen, with lesser amounts present in elastin and the C1q

component of complement. The absence of change in the total amount of

aortic collagen and noncollagen proteins suggests that the lesions may be in an

early stage of development. Sufficient time may not have elapsed to allow for a

detectable accumulation of these proteins, even though the aortas exhibit

increased rates of protein synthesis. Another possibility is that cocaine

treatment has induced both synthesis and degradation of proteins, resulting in

no net accumulation of either collagen or total proteins.

TABLE 2. Protein and collagen content in the aorta of rabbits given either

daily or alternate-day injections of cocaine

Groups

Protein Hydroxyprollne

N (mg/TH) (mg/TH)

Control

Cocaine

Responder

Nonresponder

7

8

6

6

4

3

Control

Cocaine

Responder

Nonresponder

Daily Injections

68.0±0.6 4,296±1,624

68.6±9.9 4,863±423

70.1±8.3 4,908±317

Alternate-Day Injections

73.0 ± 2.9 4,649±131

92.3±7.9 6,250±887

72.0±5.7 4,866±136

NOTE: All results are presented as mean±SE; TH=thoracic aorta.

Catecholamines are known to stimulate tissue adenyl cyclase activity that

results in increased levels of cyclic AMP. Since cocaine may produce many of

its effects by potentiating the effects of endogenous catechoiamines, aortic

levels of cyclic AMP were measured. Several studies have suggested that

159
cyclic AMP is a mediator of cellular proliferation and lipid metabolism and that

increased levels of cyclic AMP may be used as a biochemical measure of aortic

injury (Augustyn and Ziegler 1975; Chateiain 1983). Data in table 3 show a

significant increase in aortic cyclic AMP in the daily cocaine-injected rabbits in

both responders and nonresponders. Because an increase in arterial cyclic

AMP has been shown to precede the initiation of aortic protein synthesis and

collagen accumulation (Chatelain 1983) it is possible that, if we had continued

the daily injections of cocaine, all the rabbits would have shown elevated

protein synthetic rates.

TABLE 3. Aortic cyclic AMP and calcium content in rabbits given either daily

or alternate-day injections of cocaine

Group

Cyclic AMP Caldum

N (pmoles/mg Protein) (μg/mg Protein)

Daily Injections

Control

Cocaine

Responder

Nonresponder

7

8

6

6.03 ± 1.04 0.49 l 0.06

13.00 ±3.46a0.84±0.15a

13.14 ±3.36a0.57± 0.10

Alternate-Day Injections

Control

Cocaine

Responder

Nonresponder

6 5.17±1.06 0.71±0.13

4.36±0.54 0.72±0.16

5.24 ±0.91 0.49 ± 0.01

NOTE: All results are presented as mean±SE.

a

p<0.05 when compared with control group

Of the rabbits given alternate-day injections of cocaine, neither the responder

nor the nonresponder rabbits demonstrated any increase in aortic cyclic AMP

levels. It is difficult to explain why the alternate-day cocaine-treated responders

had increased rates of protein synthesis but did not have elevated levels of

cyclic AMP. One explanation may be that cyclic AMP levels are influenced by

the frequency of cocaine administration and that daily administration of cocaine

is necessary to sustain elevated tissue levels. Another possibility may be that

cyclic AMP is an early, transient cellular mediator in aortic tissues that can still

be detected at 14 days but returns to control levels by 28 days in the alternateday cocaine-treated rabbits. Additional studies are needed to clarify this issue.

160
Alteration of cellular calcium levels in vascular tissues is recognized as an

important regulatory signal involved with many cellular processes. The

accumulation of calcium has been implicated in several cellular functions such

as platelet aggregation, smooth muscle cell proliferation, and lipoprotein binding

to smooth muscle cell receptors. Elevated levels of aortic calcium have been

demonstrated repeatedly in atherosclerotic aortas and are considered to be an

indicator of cellular necrosis and cell death (Kramsch et al. 1981; Sugano et al.

1986). As shown in table 3, tissue calcium levels were significantly elevated in

the aortas of the daily cocaine treated-responder rabbits, but not in the

nonresponder animals. In the alternate-day cocaine-treated rabbits, aortic

calcium levels were not altered in either the responder or the nonresponder

rabbits. Calcium levels were determined by atomic absorption

spectrophotometry; therefore, it is not possible to discriminate between

intracellular and extracellular calcium. The presence of the increased calcium

in only the daily treated cocaine responder rabbits is significant because it

suggests that frequency of cocaine administration plays an important role in the

expression of cocaine’s toxicity. The data are also consistent with the

hypothesis that cocaine has the potential to induce alteration of aortic function,

which may possibly result in cellular necrosis and death.

7

8

6

6

4

3

The feeding of cholesterol to rabbits will cause increases in both serum and

aortic cholesterol levels. These changes then are followed by increased rates

TABLE 4. Serum cholesterol, aortic cholesterol, and visible lesions in rabbits

given daily or alternate-day injections of cocaine

Group

Serum Aortic Number of

Cholesterol Cholesterol Animals With

N (mg/100mL) (mg/TH) Viable Lesions

Control

Cocaine

Responder

Nonresponder

Control

Cocaine

Responder

Nonresponder

Dally Injections

36.6+ 4.4 0.88±0.11 1 of 8

4 of 6 38.1±9.6 1.05±0.10 1 of 6 46.5±11.1 1.03±0.16

Alternate-Day Injections

53.7± 5.6 0.89±0.05 1 of 6

67.2± 14.0 1.05±0.11 2 of 4

64.0± 2.5 0.88±0.07 1 of 3

NOTE: All results are presented as mean±SE; TH=thoracic aorta.

161
of aortic protein synthesis, increased levels of aortic cyclic AMP, and increased

aortic calcium levels. As shown in table 4, the daily or alternate-day injection of

cocaine did not cause any alteration in the final serum cholesterol levels or in

the aortic cholesterol content in either the responder or the nonresponder

rabbits. These findings suggest that cocaine has a direct effect on the aortic

wall and does not produce the observed changes by altering tissue cholesterol

levels.

As shown in table 4, of the rabbits given daily injections of cocaine, four of eight

responder rabbits and only one of the six nonresponder rabbits had grossly

visible plaques on the surface of their aortas. Of the rabbits given cocaine on

alternate days, two of four responder and one of three nonresponder rabbits

had visible plaques. in ail cases the plaques were raised patches located

primarily in the aortic arch and upper portion of the thoracic aorta. There was

no apparent difference between the visible lesions in the daily-treated and the

alternate-day-treated rabbits. Histological evaluation of the aortic tissue

sections demonstrated that cocaine-induced lesions were focal and could be

quite different. Medial lesions were the most frequent and had a spectrum of

intensity. An example of histological damage induced by cocaine administration

is shown in figure 1, which shows changes in both the intima and the media of

FIGURE 1. Photomicrograph of aorta from a rabbit injected on alternate days

with cocaine (14 injections). The lesion exhibits a necrotic area in

the media that is characterized by infiltration of inflammatory cells

and foam cells.

162
the aortic wail. in the media, there is a necrotic center that has lost its normal

morphology. The elastic fibers have lost their normal undulation and have

become either broken or replaced with inflammatory cells and foam cells. The

area above the necrotic core appears to be a thickened intima that protrudes

into the lumen of the blood vessel. Attempts to correlate changes in aortic

protein synthetic activity with histological changes were not possible. In these

studies, only limited samples were taken for histological analysis; the remainder

of the aortic tissues were used for biochemical analysis. Because of this limited

histological evaluation and because of the focal nature of the lesions, it is not

possible to determine whether the biochemically defined responder rabbits had

more medial damage than the nonresponders. It is also not possible to

determine whether a cause-and-effect relationship exists between

histopathological and biochemical changes,

The mechanism by which cocaine produced the biochemical changes in the

responder rabbits, but not in the nonresponder rabbits, is unknown. The

biochemical and histological changes produced by cocaine administration are

very similar to changes observed following epinephrine administration. It has

been suggested that epinephrine causes an increase in heart rate and blood

pressure that in some manner may cause an injury to the intimal lining of the

blood vessel (Waters and de Suto-Nagy 1950). Because cocaine has the ability

to potentiate endogenous catecholamine activity, the vessel-damaging effects

of cocaine may be the result of increased heart rate and/or blood pressure. The

exact mechanism by which increases in blood pressure and heart rate damage

the arterial wail is unknown and needs to be investigated.

The significance of our observations in rabbits to the development of aortic

damage in humans remains to be elucidated. In several cases evaluating

cocaine-induced myocardial infarctions in humans, coronary arteriography has

revealed significant vessel obstruction. In a study of patients with cocaineinduced heart disease, 9 of 13 patients who underwent cardiac catheterization

had significant stenosis of one or more coronary arteries (Pasternack et al.

1985),

Atherosclerotic cardiovascular disease is now recognized as multifactorial in

etiology (Kannel and Sytkowski 1987). Hopkins and Williams (1981) listed 246

risk factors that have been implicated in the development of atherosclerosis. it

is generally believed that the propensity to develop cardiovascular disease is

dependent on the type and number of risk factors present, duration of exposure

to each factor, and an individual’s genetically determined response to each

factor. Many epidemiological, clinical, and experimental studies have

suggested that the elimination or reduction of risk factors is necessary for the

163
prevention of atherosclerotic disease and that each risk factor makes its own

contribution and may act synergistically with other risk factors.

Our data clearly demonstrate that, in rabbits, cocaine has the ability to cause an

injury to the blood vessel wall, resulting in biochemical and morphological

changes in the arterial wall. The significance of these changes and their

relationship to cocaine-induced cardiotoxicity in humans cannot be determined

from these studies. These data, however, are consistent with the hypothesis

that the abuse of cocaine may be a risk factor in the premature onset of

atherosclerotic disease and its complications in humans who chronically use

cocaine in large amounts.

CONCLUSIONS

The results of these studies clearly demonstrate that, in sensitive animals, the

administration of cocaine has the potential to injure the vascular wall of blood

vessels, resulting in histopathological and biochemical changes. These data

are consistent with the hypothesis that cocaine abuse may directly alter the

blood vessel wall in such a manner as to induce the early onset of

cardiovascular diseases.

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ACKNOWLEDGMENT

These studies were supported in part by U.S. Public Health Service grant DA03846 from the National Institute on Drug Abuse.

AUTHORS

Ronald O. Langner, Ph.D.

Professor of Pharmacology

Collette L. Bement, Ph.D.

Research Associate

Department of Pharmacology and Toxicology

University of Connecticut

Storrs, CT 06268

166
Effects of Cocaine on the Physiology

of Exercise

Robert K. Conlee, David W Barnett, K. Patrick Kelly,

and Dong Ho Han

INTRODUCTION

It is well known that cocaine is a powerful sympathomimetlc drug (Fischman

1984). Many chapters In this monograph link the cardiotoxic effect of cocaine to

this property, which has other physiological ramifications, such as exercise

conditions, that have not been well explored. Exercise is also a powerful

sympathetic enhancer (Marker et al. 1986) and the logical questions to ask are

(1) What are the combined physiological effects of cocaine and exercise? and

(2) Could these combined effects be deleterious? Since the pioneering work of

Freud (1885) and Hanna (1970) it generally has been accepted that cocaine

may be an ergogenlc aid due to its euphoric effects (Flschman 1984). The

studies reviewed in this chapter refute that notion and provide considerable

insight into the combined physiological and metabolic responses to cocaine and

exercise.

METHODS

The following studies were performed using male Sprague-Dawiey rats that

initially weighed between 200 and 250 g. The animals were trained to run on

the motor-driven treadmill (Quinton, Seattle, WA) for 7 to 14 days before the

experiment. This pretraining involved daily sessions of running at speeds of 22

to 26 meters per minute (m/min) up a 10-percent grade for 10 to 15 minutes

duration. Three to four days before the experimental run In studies 2 and 3,

jugular catheters were implanted for delivery of cocaine and/or for

administration of the anesthetic. At the time of sacrifice, the animals were

anesthetized wlth pentobarbital sodium (60 mg/kg), and samples of blood,

skeletal muscle, or heart muscle were rapidly excised and stored frozen for

subsequent biochemical analysis. Skeletal muscle samples were obtained from

the white and red vastus lateralis muscles and the soleus muscle. These

muscles in the rat are representative of fast-twitch glycolytic, fast-twitch

oxidative, and slow-twitch oxldative fiber types, respectively (Baldwin et al.

1972).

167
Study 1. Effects of Cocaine on Endurance

Design. The purpose of the study by Bracken and colleagues (1988) was to

determine if cocaine had an enhancing effect on endurance. Animals were

injected intraperitoneally (IP) with cocaine (20 mg/kg) or isotonic saline and,

beginning 20 minutes after injection, were run to exhaustion (22 m/min, 15-

percent grade). This dose of cocaine was selected because Kershner and

coworkers (1983) reported that it improved performance in their study.

Results. The cocaine-treated rats ran only 29±12 minutes compared to 75±17

(x±D) minutes for the saline-injected controls. Clearly, cocaine had a

detrimental effect on performance. To understand the cause of the poor

performance in the cocaine group, the glycogen content of the three different

skeletal muscle fiber types common to the rat was analyzed. Glycogen is an

important energy substrate in skeletal muscle, and any change in its

concentration during exercise usually reflects muscle involvement (Conlee

1987). These results are shown in figure 1. It was clear that in the two fasttwitch muscles (red and white vastus) of the hind limb, glycogen appeared to be

used at a much greater rate in the cocaine group than in the saline group.

Since glycogen depletion is known to cause fatigue (Conlee 1987), the rapid

use of glycogen in the cocaine-treated animals could have led to premature

fatigue. On the other hand, when blood lactic acid levels were measured in

these animals (figure 2) the values in the cocaine-treated animals were more

than twice as high as those in the saline-treated group. This observation alone

could explain the early fatigue in the drug-treated group. By some unknown

mechanisms cocaine caused rapid glycogenolysis and concomitant

lactacidemia, both of which could have contributed to early cessation of

exercise. Some possible mechanisms are proposed in the discussion of studies

1 and 2.

Study 2. Effects of Various Doses of Cocaine on Exercise Endurance and

Physlology

Design. The second study by Bracken and coworkers (1989) tested the effects

of a wide range of doses on exercise endurance and gathered more

physiological information that might help to clarify the observations of the first

study. Animals were injected IP with saline or 0.1, 0.5, 2.5, 12.5, or 20 mg/kg

cocaine and then, beginning 20 minutes after the injection, were run to

exhaustion (26 m/min, 10-percent grade).

Results. Figure 3 shows the endurance results. Cocaine had no beneficial

effect on endurance at any dose. At the two highest doses, cocaine severely

limited endurance. The muscle-glycogen results from the dose-response study

168
FIGURE 1. Effect of cocaine and exercise on glycogen concentration in

soleus, red vastus lateralis, and white vastus lateralis muscles of

the rat

NOTE: Each point=mean±SE for five to seven animals. Exhausted values are

significantly different from preexercise values, p<0.05.

SOURCE: Bracken et al. 1988, copyright 1988, American Physiological

Society.

169
Blood Lactate

FIGURE 2. Effect of cocaine and exercise on blood lactate levels

NOTE: Each bar=mean±SE for five to seven animals.

*Significantly different from at rest

+Significantly different from saline, p<0.05

SOURCE: Bracken et al. 1988, copyright 1988, American Physiological

Society.

are shown in figure 4. Across all doses, cocaine treatment had no effect on

resting glycogen content of the two predominantly fast-twitch muscles (white

and red vastus lateralis). However, the two highest doses caused a reduction in

the glycogen concentration in the slow-twitch soleus muscle at rest. This effect

on soleus muscle at rest may reflect an Increased locomotor activity often

observed in cocaine-treated animals (Post and Weiss 1988). At exhaustion, the

glycogen levels in all muscles for all treatments were reduced to the same

levels (figure 4), but because the cocaine animals (12.5 and 20.0 mg/kg) ran for

a considerably shorter time (figure 3), it was concluded that the rate of glycogen

depletion in those animals was greater.

170
FIGURE 3. Run times to exhaustion of rats Injected with five different doses

of cocaine and run at 26 m/min up a 10-percent grade

NOTE: Each bar=mean±SE; n=7 to 11 animals for each group.

*Significantly different from 0 dose (saline-treated controls), p<0.05

SOURCE: Bracken et al. 1989, copyright 1989, American Physiological

Society.

Blood levels of epinephrine (E) and norepinephrine (NE) also were measured,

and those results are shown in figure 5. Both amines showed a tendency to

rise with increasing dose at rest. However, the increase was more dramatic for

NE than E. During exercise, cocaine (20 mg/kg) clearly exaggerated the NE

response, but the effect on E was less discernible. This latter result with E was

more attributable to the design of the study than to a lack of effect of cocaine.

in the last phases of an exhausting run, all animals tended to fall more often on

the electric grid attached to the treadmill, which created an additional stress in

the animal. Such additional stress in the saline animals could have

exaggerated the catecholamine response and masked the real physiological

effect of exercise alone (Marker et al. 1986). This opinion is supported by the

171
FIGURE 4. Effect of various doses of cocaine on hind limb muscle glycogen

content before (pre) and after (post) treadmill exercise (26 m/min,

10-percent grade) to exhaustion

NOTE: Each bar=mean±SE; n=7 to 11 animals for each group.

*Significantly different from corresponding preexercise value, p<0.05

+Significantly different from preexercise 0 dose (saline-treated controls)

SOURCE: Bracken et al. 1989, copyright 1989, American Physiological

Society.

172
FIGURE 5. Effect of various doses of cocaine on plasma concentration of

norepinephrine and epinephrine before (pre) and after (post)

treadmill exercise (26 rn/min, 10-percent grade) to exhaustion

(see figure 4 legend for details)

Significantly different from postexercise 0 dose, p< 0.05

SOURCE: Bracken et al. 1989, copyright 1989, American Physiological

Society.

173
results in table 1, which were obtained from exhausted cocaine animals and

paired-saline runners. It is clear that running for the same period results in

higher NE and E values in the cocaine-treated animals compared to paired

saline-treated rats. A marked contrast in lactate values also was observed

between groups, similar to that shown in figure 2.

TABLE 1. Comparison of plasma catecholamine and blood lactate levels

from cocaine-treated fatigued rats and saline-treated, time-paired

control runners

Cocaine

Norepinephrine Epinephrine

(pg/mL) (pg/mL)

2,992* 1,445

±563 ±444

Lactate

(mM)

10.5*

±2.4

Saline 648 616 2.4

±237 ±230 ±0.1

NOTE: Values=means±SE; n=five to six animals for each group.

*Significantly different from paired saline runners

SOURCE: Bracken et al. 1989, copyright 1989, American Physiological

Society.

These results imply that cocaine dramatically exaggerates the normal

sympathetic response to exercise, but the data in table 1 still can be criticized

because they were obtained from cocaine animals being forced to run to

fatigue, which, as alluded to earlier, may have additional physiological

consequences above those derived from cocaine or exercise alone. With that

in mind, another experiment was designed in which animals were injected with

cocaine (12.5 mg/kg) or saline and then run for only 30 minutes. The animals

were in a more steady-state regimen, thus eliminating the confounding factors

associated with running to exhaustion. The preliminary results (unpublished

observations) verify that the normal rise in plasma concentrations of E and NE

during exercise is accentuated dramatically by cocaine. These are exciting

observations of the peripheral physiological responses to cocaine. Because of

these additive responses, it appears that the exercise model eventually could

serve as an important research tool for studying the mechanisms by which

cocaine exerts its effects.

174
Discussion of Studies 1 and 2

It is clear from studies 1 and 2 that cocaine has an adverse effect on prolonged

exercise endurance. The physiological and biochemical observations made

concomitantly with the endurance results suggest some possible mechanisms

by which cocaine exerts its influence.

1. Cocaine is known to induce vasoconstriction in a variety of tissues (Ritchie

and Greene 1980). This can occur indirectly because cocaine inhibits the

reuptake of NE at sympathetic presynaptic terminals (Herting et al. 1961).

An accumulation of NE in the synaptic space could induce vasoconstriction

of arterioles through alpha receptors (Belfrage and Rosell 1976). If this

happened in muscle during exercise, there would be reduction of blood

flow, decreased delivery of oxygen, increased rate of glycogenolysis for

energy, and eventual increase in lactic acid production, On the other hand,

vasoconstriction also can occur as a seemingly direct effect of cocaine on

the vasculature without any intervening hormonal or neurotransmitter

response (Shuster et al. 1988). Whether direct or indirect, the

vasoconstrictlon could lead to fatigue through the cascade of responses

outlined above, with fatigue being the result of glycogen depletion or lactic

acid accumulation (Conlee 1987).

2.

3.

The increased muscle glycogenolysis observed during exercise performed

under the influence of cocaine could result from the effect of higher levels

of E induced by the cocaine. Epinephrine during exercise is known to

stimulate muscle glycogenolysis (Richter et al. 1981). A wasting of

glycogen could lead to early fatigue (Conlee 1987).

It is possible that cocaine may stimulate glycogenolysis directly, although

there is no evidence to support this contention,

Study 3. Effects of Cocaine on Cardiac Metabolism

Design. The study by Conlee and colleagues (1989) was designed to evaluate

the combined effects of exercise and cocaine on myocardial carbohydrate

metabolism as a logical extension of the authors’ results from skeletal muscle.

Animals were injected intravenously with either saline or one of three doses of

cocaine (1.25, 5.0, or 10.0 mg/kg). It is important to point out some

methodological considerations. In the preliminary work for this study, the

authors found that single, rapid, bolus intravenous injections of cocaine caused

seizures and, sometimes, death; 20 mg/kg was almost always fatal, and that

dose was abandoned. After trial and error, a satisfactory injection scheme was

established. The proper dose was delivered in a volume of 0.2 mL/100 g BW

175
(body weight) administered in six to eight small bolus injections over a 3-minute

period while the animal was restrained by hand. Saline-treated animals were

injected in exactly the same manner. Using this protocol, only two cocaineinjected animals were unable to begin running immediately after injection, and

they were eliminated from the study. The treadmill protocol consisted of a 20-

minute run at 22 m/min and 15-percent grade. Upon cessation of the run, the

animals were anesthetized immediately (20 seconds), and the hearts were

removed and frozen within 10 seconds of opening the thorax.

Results. Unlike the results with skeletal muscle (figures 1 and 4), there was no

effect of cocaine on myocardial glycogen concentration at rest or exercise

(figure 6). Nor was there any effect of the drug on the concentration of glucose6-phosphate in the myocardium (figure 6). These results contrast to the

dramatic dose-response increases seen In plasma-free fatty acids (figure 7).

Discussion of Study 3

Recent reports have temporally linked incidents of myocardial infarcts to the use

of cocaine (Altieri et al. 1987; Zimmerman et al. 1987). One mechanism

proposed to explain the seizures was the cocaine-induced vasoconstriction of

the coronary vasculature. Support for this theory derives from two sources.

First, Wilkerson (1989) showed that in dogs under the influence of cocaine,

myocardial blood flow did not keep up with myocardial oxygen demand.

Second, Lange and coworkers (1989) recently observed in humans that

cocaine reduced the size of coronary arteries and caused vasoconstriction of

the intramural resistance vessels. It could be reasoned that, because the use

of stored glycogen for energy by the myocardium is closely linked to oxygen

availability (Hewitt et al. 1973), any decrease in oxygen delivery due to cocaineinduced vasoconstrlctlon could Increase glycogen degradation, especially

during exercise when oxygen demand is high. Unfortunately, no alteration of

carbohydrate metabolism due to cocaine was observed. This would argue

indirectly against the notion that cocaine interferes with blood flow to the

myocardium. This does not mean, however, that cocaine may not have an

effect under different experimental conditions (e.g., longer or more intense

exercise). On the other hand, it may be that cocaine acts only on hearts that

are uniquely susceptible to the drug. Evidence presented elsewhere in this

monograph (Langner and Bement; Knuepfer et al.) supports the theory that not

all organisms are responders. This is empirically true when one considers that

only a small fraction of cocaine users ever experience a cocaine-induced heart

seizure (Choy-Kwong and Lipton 1989). Nevertheless, preliminary results show

an exaggerated sympathetic response to cocaine and exercise, which suggests

that the two conditions combined may create a set of physiological conditions

that could be detrimental to individuals predisposed to cardiovascular disorders.

Whereas this point is speculative, it deserves further study.

176
FIGURE 6. Effects of various doses of cocaine after 20 minutes of exercise

(22 m/min, 15-percent grade) on myocardial glycogen and

glucose-6-phosphate concentrations

NOTE: Each bar=mean±SE; n=4 to 13 animals for each group.

No significant differences were observed among any treatments, p>0.05.

SOURCE: Conlee et al. 1989, copyright 1989, W.B. Saunders Company.

177
FIGURE 7. Effects of various doses of cocaine after 20 minutes of exercise

(22 m/min, 15-percent grade) on plasma-free fatty acid levels

NOTE: Each bar=mean±SE; n=7 to 13 animals for each group.

* Significantly different from 0 dose (saline controls), p<0.05

+Significantly different from at rest

Significantly different from other two cocaine doses, p<0.05

SOURCE: Conlee et al. 1989, copyright 1989, W.B. Saunders Company.

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ACKNOWLEDGMENTS

This work was supported in part by Faculty Fellowship Funds and the ASBYU at

Brigham Young University and by U.S. Public Health Service grant DA-04382

from the National Institute on Drug Abuse.

AUTHORS

Robert K. Conlee, Ph.D.

Professor

David W. Barnett, Ph.D.

Assistant Professor

K. Patrick Kelly, M.S.

Dong Ho Han, M.S.

Exercise Biochemistry Laboratory

Department of Physical Education Sports

Brigham Young University

116 Richards Building

Provo, UT 84602

180
Effect of Acute Cocaine Administration

on Cardiac and Respiratory Patterning

in the Freely Moving Cat

Ronald M. Harper, Rebecca K. Harper, Robert R. Terreberry,

Christopher A. Richard, and Robert B. Trelease

INTRODUCTION

Mechanisms underlying cardiovascular and respiratory changes following acute

cocaine administration are extremely complex, since cardiovascular responses

associated with cocaine administration are most likely dependent on drug action

on both the peripheral and central nervous system (CNS). Moreover,

respiratory and cardiovascular control systems are highly interactive, with

changes in one system being associated with alterations in the other.

Exaggerated inspiratory efforts, for example, are accompanied by enhanced

venous return, which in turn triggers a set of cardiac reflexes, whereas rapid

transient increases in arterial pressure can diminish somatic muscle tone and

lead to short-term abolition of inspiratory efforts.

It is essential to understand both cardiovascular and respiratory control

mechanism responses to cocaine, since high-dose acute cocaine administration

is lethal. Death may result from apnea or apneusis, from some failure of

cardiovascular function, or from some interaction of the two systems such as

respiratory compromise leading to hypoxia, which then leads to an agonal

cardiac rhythm. It is also essential to consider potential effects of cocaine on the

CNS and how these effects may modify the interactions between respiratory

patterning and the cardiovascular system. Cocaine has been shown to have a

particular affinity for action on limbic forebrain structures (Jones 1984), which

have major direct influences on cardiovascular action in intact systems.

The role of neural mechanisms in controlling respiration outside of central and

peripheral chemoreceptors frequently is ignored, yet brain structures—in

particular, rostral brain structures—can have profound effects on respiratory

patterning. Although cyclic respiratory patterns and adequate blood pressure

181
can be maintained in a preparation with suprapontine transection (Hoff and

Breckenridge 1952), descending forebrain influences can greatly influence both

cardiac and respiratory control structures (Frysinger et al. 1984; Marks et al.

1987).

Obvious instances of such higher brain influences include voluntary breathing,

vocalization, temperature drive to respiration, and sleep states. In particular,

sleep states, when combined with certain pathological conditions, can suppress

normal respiratory patterning in some or all of the ventilatory musculature, for

example, in central and obstructive sleep apnea (Severinghaus and Mitchell

1962; Harper and Sauerland 1978; Remmers et al. 1978). This suppression is

thought to be initiated in pontine structures, which provoke atonia of respiratory

muscles mediated through medial reticular structures in the caudal medulla

(Schenkel and Siegel 1989). Cocaine may exert deleterious effects on the

functions of particular brain structures that project to cardiac and respiratory

control mechanisms in the brainstem, thus disturbing normal respiratory and

cardiovascular control.

The available evidence on respiratory patterning after cocaine intoxication is

sparse. Rapid shallow breathing (Wilson et al. 1976; Matsuzaki et al. 1978) and

apnea have been reported: the latter frequently is observed following

generalized convulsions (Catravas and Waters 1981; Jonsson et al. 1983).

Clinical reports of acute cocaine intoxication suggest that respiratory “failure” is

a frequent finding.

It is important to determine whether cocaine-related “failure” of respiration

results from diminished activation of the diaphragm or whether “failure” results

from (1) obstruction of the upper airway caused by extreme excitation of

laryngeal adductors (“active obstruction”), (2) extreme sustained inspiratory

effort by the diaphragm (apneusis) so prolonged as to cause a loss of O2

 stores,

(3) collapse of the upper airway brought about by drug-induced loss of upper

airway muscle tone and the consequential airway narrowing from the Venturi

effect of negative diaphragmatic pressure (Harper and Sauerland 1978), or (4) a

tachypnea of such enhanced rate as to make airflow ineffective. The reports

that rapid, shallow respiration accompanies cocaine intoxication suggest that

cocaine exerts a major effect on central respiratory timing mechanisms.

However, the potential for active upper airway occlusion or sustained inspiration

of the diaphragm exists, particularly as a consequence of localized limbic

system seizure discharge.

Determining the mechanisms of cocaine action on different respiratory muscles

is important because different mechanisms of action have an impact on toxic

182
management. Our first studies examined the action of high-acute doses of

cocaine on upper airway and diaphragmatic patterning and potential interactivity

with the cardiovascular system.

METHODS

These studies have been carried out on two female and three male adult cats.

Under sodium pentobarbital anesthesia, a pair of insulated, flexible,

multistranded stainless steel wires were placed into the posterior cricoatytenoid

(PCA) muscles of the larynx, an upper airway dilator muscle, and four sets of

wires were placed into the lateral costal diaphragm (figure 1). Bipolar stainless

FIGURE 1. Schematic outline of the principal measures taken from the

subjects. Electromyographic activity of a laryngeal dilator, the

PCA, and the costal diaphragm are recorded. ECG activity and

hippocampal and cortical slow wave electrical activity also are

measured.

183
steel electrodes also were stereotaxically placed bilaterally into the dorsal

hippocampus (Snider and Neimer 1961), and stainless steel screws were

placed into the bone overlying the sensorimotor cortex. These hippocampal

and surface electroencephalogram (EEG) electrodes were placed to record

limbic system and cortical electrical activity, respectively, particularly during

cocaine-related seizure discharge. A thermistor was placed on the cortex over

the parietal cortex, and another thermistor was placed in muscle between the

clavicles to record brain and core body temperature, respectively. Stainless

steel cannulae, covered at one end, were placed within the lateral ventricle.

Electrocardiogram (ECG) activity could be recorded from the same respiratory

leads placed in the diaphragm (figure 1); however, this diaphragm-lead

configuration does not readily provide indications of atrial pulses. For this

reason, we also placed a 4-5 French five-pole recording catheter through the

right jugular vein into the right ventricle so that atrial and ventricular activity

could be recorded. Moreover, these recordings were supplemented by surface

recordings with an electrode placed high on the right thoracic cage and low on

the left abdominal wall to assist in P-wave differentiation on the ECG trace.

After 2 weeks of surgical recovery, the animals were placed in a soundattenuated 1 m

3

 recording chamber kept at room temperature. Electrodes were

attached to a polygraph, and signals were simultaneously written on polygraph

paper, digitized at appropriate rates as dictated by the Nyquist frequency

(Harper et al. 1974), and stored on digital media as well as on analog tape.

After a control recording of one sleep and waking cycle, the subjects were

administered one of three doses of cocaine intravenously (5.0, 7.5, or 10.0 mg/

kg or an equivalent volume of saline) or, in the case of ventricular

administration, 0.625, 1.25, or 2.5 mg or an equivalent volume of artificial

cerebrospinal fluid for control studies. Cortical EEG, hippocampal slow activity,

ECG, PCA and diaphragmatic patterning, and brain temperature were all

recorded and stored on digital and analog media. Diazepam (10 mg

administered intravenously) was used to intervene in those cases in which

cardiac arrhythmias appeared to be proceeding to sustained ventricular

tachycardia or agonal rhythm.

RESULTS

Motor Characteristics

High-dose cocaine administration resulted in an extreme extension of the limbs

and neck and arching of the back reminiscent of decerebrate rigidity (figure 2).

This extreme extension was accompanied by clonic jerks associated with

seizure discharge. A similar state (without seizures) can be produced in

animals with lesions In the Interstitial nucleus of Cajal (Fukushima et al. 1987)

184
or with decerebration involving loss of cortical and basal ganglion structures, the

classic preparation for decerebrate rigidity (Sherrington 1898). The pronounced

motor extension produced by cocaine is of great theoretical and practical

interest, since these findings raise the possibility of generalized involvement of

much of the skeletal musculature, including the respiratory musculature.

Moreover, the findings suggest action of cocaine on specific neural mechanisms

controlling motor systems, and these actions can be experimentally partitioned.

The extreme motor signs diminished 1 to 2 hours after cocaine administration,

although animals had difficulty with motor behavior for an additional several

hours. The motor expression is similar to that described in sheep following

cocaine administration (Woods et al. 1989) and has been anecdotally reported

in humans. Other autonomic motor behavior accompanies the somatic motor

FIGURE 2. Typical posture following high-dose administration of cocaine

(although the animal is lying on one side). This is a modification

of an original drawing of decerebrate rigidity by Pollock and Davis

(1930). The neck, back muscles, and limbs are in extreme

extension; this motor behavior also is accompanied by periodic

(12 per minute decreasing to approximately 9 per minute and then

ceasing) myoclonic jerks.

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changes. The animals salivate profusely 5 to 30 minutes following drug

administration, typically vomit 20 to 30 minutes after intravenous (IV)

administration, and have a bowel movement 30 minutes to 1 hour after initial

onset of drug action.

Respiration

The major cocaine effect on both upper airway and diaphragmatic activity after

the initial extreme rise In blood pressure is tachypnea. The rise in discharge

rate is extreme, and the resulting gas exchange may be ineffective for survival.

We have not yet assessed tissue oxygen saturation following cocaine, but the

animals show every sign of being hypoxic, including the mode of death (agonal

rhythm). The rise in rate occurs in the PCA and diaphragmatic muscles. We

also have not as yet determined whether the relative timing of activation of the

PCA vs. the diaphragm is affected by cocaine; a derangement of phase

between these two muscle systems might greatly affect air exchange,

particularly if the airway were occluded when the diaphragm is in the inspiratory

phase.

In addition to the initial increase in both upper airway (PCA) and dlaphragmatic

muscle activity rate [in 3 some cases by a factor of four over normal baseline

waking rates (figure 3)], cocaine administration was followed by a pronounced

phasic increase in upper airway muscle activity, particularly of the genioglossal

muscles of the tongue; moreover, panting occurred later (1 to 2 minutes post

administration) in the recording session. These changes may be associated

partially with temperature increases (see below) since there was a delay in the

onset of the enhanced upper airway effect. Increased activation of airway

dilators would assist in lowering core temperature by enhancing air movement.

Temperature

An increase in core and brain temperature occurred following administration of

cocaine by any route (figure 4). Brain temperature increased markedly and

rapidly following IV administration (average increase of 0.85°C in 30 minutes).

A slight, gradual increase then followed, reaching a maximum temperature

within 1 1/2 to 2 hours post intravenous injection (1.2°C mean increase over

baseline, five cats); temperature then declined slowly, returning to baseline

typically 2-1/2 to 3 hours following initial cocaine administration. lntracerebral

ventricular administration resulted in a sharp rise in temperature, reaching a

maximum 8 to 15 minutes post injection (0.7°C average), with a steady decline

thereafter and return to normal baseline in 30 minutes.

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FIGURE 3. Root-mean-square (a close analog of integration) traces of PCA

activity before cocaine administration, 15 minutes following 7.5

mg/kg administration, and 3 hours postadministration.

Respiratory bursts increase by a factor of four over control

periods; diaphragmatic bursts occur equally as often.

A portion of the tachypnea observed following cocaine administration may result

from the increased temperature noted here, since increased respiratory rates

result from increases in core temperature and the extreme respiratory efforts in

panting may serve to diminish core temperature. We still are partitioning the

effect of temperature on respiratory patterning, relative to a direct effect of

cocaine on brain structures that act directly on respiratory timing structures.

Cardiac

Examination of cardiac R-R intervals before cocaine administration revealed

typical variation at the respiratory frequency as well as slower variation from

movement, blood pressure variation, and temperature trends; the slower

variation was particularly prominent during rapid eye movement (REM) sleep,

and the respiratory variation was especially large during quiet sleep. Following

cocaine administration, R-R intervals became fixed, with a total abolition of both

respiratory and slower variation. Both types of variation gradually returned after

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FIGURE 4. Plot of trend in brain temperature (measured by an indwelling

thermistor and continuously monitored by an analog voltmeter

and then digitized) following administration of 10 mg/kg cocaine.

Brain temperature reached a peak approximately 25 minutes post

administration. A 10 mg IV administration of diazepam caused a

second rise in temperature (possibly mediated by handling),

followed by a more rapid decrease.

several hours, with slower variation returning first (figure 5). The overall R-R

interval duration decreased (i.e., heart rate increased) following cocaine

administration; this heart rate increase gradually declined over time. In addition,

R-R interval durations and variation increased immediately following diazepam

administration (figure 8).

Large cocaine doses, administered intravenously, resulted in a variety of

cardiac arrhythmias, including ventricular tachycardia. The largest IV cocaine

doses typically resulted in generalized tonic seizure-like discharges that were

characterized by extreme extension of the peripheral musculature typical of

decerebrate rigidity described earlier. One seizure was accompanied by a

widened QRS complex recurring at a very rapid rate with a period that matched

the synchronized electrical activity recorded from the hippocampus (figure 7).

Administration of the benzodiazepine diazepam (10 mg) caused an immediate

(within 30 seconds) return of hippocampal activity to nonseizure state and a

concomitant conversion of the arrhythmia to a sinus rhythm (figure 8). Two

animals that received high-dose cocaine in which diazepam intervention was

ineffective succumbed to an agonal rhythm, which classically results from

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hypoxia. Death from hypoxia typically occurs in an agonal rhythm rather than

ventricular fibrillation. Thus, cocaine may so constrict the vasculature as to

cause hypoxia or may impair respiratory efforts, which in turn leads to hypoxia.

FIGURE 5. Plot of cardiac R-R intervals before 7.5 mg/kg IV cocaine

administration, 30 minutes post administration, and 3 hours post

administration. R-R interval times in msec are on the y axis;

successive intervals are on the x axis. Approximately 2 minutes

of intervals are shown on each trace. Note the near flat line

indicating virtually no variation 30 minutes after cocaine

administration; the scale indicates 10 msec above and below 110.

Cocaine administration initially was followed by an extreme rise in pressure and

thus a pronounced baroreflex-initiated extreme vagal outflow. This enhanced

vagal outflow was sufficient to alter conduction (figure 9).

DISCUSSION

The objectives of these studies were to examine the effect of acute

administration of cocaine on upper airway and diaphragmatic respiratory

musculature in the freely moving, conscious cat, to relate respiratory patterning

in these muscles to electrical activity in limbic structures of the brain, and to

examine cardiorespiratory interactions. Specific questions addressed by these

189
FIGURE 6. Compressed record of R-R intervals plotted over an 80-minute

period before administration, following cocaine delivery (bar), and

following delivery of diazepam (second bar). Note the extreme

shortening of R-R intervals (cardiac rate increase) and the virtual

abolition of variation in these intervals following cocaine

administration and the rapid return to longer intervals (slower rate)

and increased variation following diazepam delivery.

studies included examining the hypotheses that (1) cocaine exerts preferential

enhancement of upper airway constrictors, thus potentially leading to upper

airway obstruction and (2) cocaine causes extreme apneustic activity In the

diaphragm, thus leading to a fall in O2 stores. A second objective was to relate

patterning of cardiovascular activity to electrical activity in brain structures and

to partition the effect of cardiovascular changes secondary to respiratory

changes induced by cocaine. Specifically, we wished to test the hypothesis that

seizure discharge, particularly in limbic structures, provided such profound

neural drive to cardiac innervation as to greatly modify cardiac conduction

patterns. Moreover, we wished to examine the possibility that cocaine effects

would greatly modify normal cardiorespiratory reflexes protective of

cardiovascular function.

190
FIGURE 7. ECG traces (recorded from two diaphragm leads) together with

tracings from bipolar hippocampal leads during cocaine seizure

discharge. The QRS complexes are extremely wide and recur at

rapid rates. Note the close temporal relationship of discharge in

the hippocampus with ECG activity.

Acute administration of cocaine had a marked effect on patterning of upper

airway and diaphragmatic respiratory musculature. Although apneic and

apneustic episodes occurred, the most common respiratory effect was a

tachypnea superimposed on increased tonic levels of activity In respiratory

musculature. The cocaine effects extended not only to rate but also to greatly

enhanced recruitment of at least upper airway dilators. The latter effect may be

secondary to heat dissipation attempts to accommodate the pronounced rise in

core temperature; however, the possibility of generallzed recruitment that might

include airway constrictors as well as dilators cannot be overlooked.

Cocaine also had a marked effect on cardiac rate and variation. Rate was

increased and variability virtually eliminated following cocaine administration,

with a complete abolition of both respiratory-related and slow variation. A most

unexpected and provocative finding was the entrainment of a ventricular

arrhythmia with synchronous EEG discharge in the hippocampus accompanying

a cocaine-induced seizure and the immediate conversion to a normal cardiac

and EEG rhythm with diazepam. This finding suggests that cocaine-induced,

191
FIGURE 8. ECG and hippocampal traces recorded during the recovery

period. The coupling between hippocampal activity and ECG

activity has diminished.

seizure-like discharge may modify baroreflexes, output of the nucleus ambiguus

to the vagus, or output to the intermediolateral sympathetic column, all

modifications that would alter neural influences on the myocardium. The

implication is that disruption of cardiac rhythm control may be accomplished in

part by modification of CNS activity rather than by control of peripheral actions

alone.

Our data on cocaine-induced elevations in heart rate confirm previous findings

(Ritchie and Greene 1980; Resnick et al. 1977; Wilson et al. 1976; Fischman et

al. 1976, 1983). Myocardial infarctions and symptomatic ischemia frequently

have been associated with vasoconstriction (Coleman et al. 1982; Schachne et

al. 1984; Kassowsky and Lyon 1984; Cregler and Mark 1986).

A portion of the cardiovascular changes may be determined indirectly by

respiratory pattern changes. Cocaine may exert action on CNS structures that

mediate respiratory patterning or may affect thermoregulatory structures that

can modify respiration indirectly. This action of cocaine on respiratory

patterning may indirectly modify the cardiovascular responses of classic

192
FIGURE 9. ECG traces 1 minute post administration of 10 mg/kg cocaine

administered intravenously. “A" and “B” are continuous,

successive traces. The high sympathetic tone results in cardiac

conduction changes together with high rate; a short burst of

ventricular tachycardia (bar marked VT) is noted and is later

followed by AV dissociation with junctional escape rhythm (dotted

line), presumably as a consequence of concurrent high vagal

lone.

cardiopulmonary reflexes. Cocaine greatly increases diaphragmatic discharge

rate, with potentially diminished effective tidal volume: the net effect is probably

(although as yet unmeasured) reduced air exchange and the potential for

hypoxia. The resulting hypoxia then can lead to a variety of cardiovascular

sequelae. In addition, mechanical aspects of the resulting tachypnea will cause

dramatic changes in simple cardiovascular dynamics such as venous return,

which is partially dependent on respiratory efforts. Respiratory modulation of

cardiac R-R intervals disappears under tachypnea, as is the case in these

recordings (although the rapid heart rates also contribute to the disappearance

of any respiratory modulation).

Changes in respiratory mechanics can alter cardiovascular action, but

cardiovascular action also interacts with respiratory patterning. For example, a

rapid rise in arterial pressure from basal levels of pressure is associated with a

rapid and pronounced suppression of diaphragmatic activity (Trelease et al.

1983) and an even more pronounced suppression of upper airway dilator

193
musculature activity (Marks and Harper 1987). Such reflexes serve as

important protective mechanisms to prevent further rises in pressure from

venous return assisted by respiratory movements but under certain conditions

(e.g., those associated with obstructive sleep apnea) may prolong an existing

suppression of respiratory movements. The implications for cocaine effects are

that the rapid rise in arterial pressure may directly suppress respiratory activity.

Control of core temperature and sympathetic drive to the vasculature are

interrelated. Cocaine-related hyperthermia (Wilson et al. 1976) may result

partially from the lack of heat dissipation concomitant with extreme

vasoconstriction and partially from cocaine actions on anterior hypothalamic

and brainstem temperature-regulating areas. Elevated core temperature will

profoundly affect respiratory rate: thus, a cocaine-related accelerated

respiratory rate may result partially from hyperthermia-induced excitation of

pontine phase-switching mechanisms.

A prominent characteristic of high-dose cocaine was the occurrence of seizures,

which were prominent in limbic regions such as the hippocampus. Cocaine

appears to have a special affinity for altering activity in limbic system structures,

particularly in amygdaloid regions (Jones 1984). Although high levels of

cocaine can elicit generalized convulsions (Catravas and Waters 1981; Myers

and Earnest 1984), lower levels can elicit focal seizure discharge in the

amygdala to the extent that cocaine-induced amygdaloid seizures have been

proposed as a model for temporal lobe epilepsy (complex partial seizures)

(Eidelberg et al. 1963). Cocaine lowers the current threshold necessary to

Induce kindled afterdischarge activity In the amygdala and hippocampus (Lesse

and Harper 1985). Cocaine increases the speed with which afterdischarge

activity spreads to amygdaloid and hippocampal structures ipsilaterally and

contralaterally from stimulation-elicited afterdischarge. Kindled seizure

discharge within the central nucleus of the amygdala (ACE) results in profound

cardiac and respiratory pattern changes, with prolonged apneusis and extreme

tachycardia (Harper 1986). Partial seizures of focal temporal lobe origin are

accompanied typically by tachycardia and are associated frequently with a

variety of respiratory pattern disturbances, including obstructive apnea

(Frysinger et al. 1987). Since cocaine intoxication results in localized

amygdaloid seizures, the direct central limbic effects on respiratory and

cardiovascular activity may be profound.

Particular structures within the limbic system, especially the ACE, can exert

profound effects on cardiovascular and respiratory activity. Single-pulse

electrical stimulation of the ACE at a rate slightly faster than the resting

respiratory rate entrains respiration, an effect that is abolished in sleep (Harper

et al. 1984). Train electrical stimulation of the ACE elicits a marked elevation in

194
arterial pressure, a relationship that is abolished in REM sleep, together with a

pronounced apneusis (Frysinger et al. 1984). A proportion of ACE neurons

discharge in phase with the respiratory cycle (Zhang et al. 1986a) and with a

tonic discharge relationship with respiratory rate or arterial pressure (Frysinger

et al. 1988), while bilateral cold-blockade of the ACE results in abolition of an

aversively conditioned blood pressure and respiratory response (Zhang et al.

1986b).

It is particularly appropriate to address the role of the ACE in respiratory and

cardiac regulation following cocaine intoxication, considering the anatomical

relationships between the ACE and the nucleus accumbens (NA) in the ventral

forebrain. The NA is considered to be part of the ventral (Heimer and Wilson

1975; Heimer et al. 1982) or “visceral” (Jayaraman 1985; Neafsey and

Terreberry 1986) striatum and has a significant role in control of cocaine selfadministration (Roberts et al. 1980; Zito et al. 1985) and amphetamine-induced

locomotion (Vaccarino et al. 1986). The ACE, the lateral portion of the bed

nucleus of the stria terminalis, and the medial portion of the NA contain a

rostral-caudal continuum of neurons in the basal forebrain (Heimer et al. 1985;

Zaborszky et al. 1985). The NA also receives a heavy midbrain dopaminergic

input from A9 and A10 (Fallon and Moore 1978; Hokfelt et al. 1980). The ACE

projects heavily to A8 and lateral A9 dopaminergic cells of the midbrain, rostral

locus coeruleus (A6) noradrenerglc neurons, and the adrenergic (C2) and

noradrenergic (A2) cells within the nucleus of the solitary tract (Wallace et al.

1989). These projections provide the functional substrate for cocaine to modify

cardiovascular action by central mechanisms.

The NA (Nauta et al. 1978) and the ACE (Hopkins and Holstege 1978) project

to the nucleus parabrachialis medialis of the pons (NPBM), the latter projection

being massive. The NPBM forms part of the so-called “pneumotaxic area”

(Cohen 1971), which contains cells that discharge phasicaily with the

respiratory cycle (Lydic and Orem 1979; Sieck and Harper 1980) on a staterelated basis (Harper and Sieck 1980), and is heavily involved wlth respiratory

phase switching. Stimulation of this area elicits premature transition from

inspiration to expiration and can pace respiratory rate (Bassal and Bianchi

1982). The NPBM lesions in vagotomized preparations result in prolonged

apneusis (Bertrand and Hugelin 1971; Cohen 1971; St. John et al. 1972;

Gautier and Bertrand 1975; Euler et al. 1976) whereas NPBM lesions in the

intact cat result in apneas during quiet sleep that are accentuated in REM sleep

(Baker et al. 1981). This area also plays a role in regulation of blood pressure

and bradycardia (Hamilton et al. 1981; Mraovitch et al. 1982). Thus, the

potential exists for cocaine action on the ACE to greatly modify blood pressure

and respiratory pattern. Seizure discharge within the ACE might potentiate

effects on brainstem sites.

195
CONCLUSIONS

These studies suggest pronounced effects of cocaine on respiratory

musculature and interaction between temperature, respiration, and

cardiovascular control systems. Moreover, seizure discharge in rostral brain

areas may elicit substantial cardiovascular effects. Cocaine has the potential to

alter action in many homeostatic mechanisms, and many of these perturbations

have lethal consequences.

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ACKNOWLEDGMENTS

This research was supported by National Institute on Drug Abuse grant DA04913. Richard Verrier, Ph.D., provided advice on ECG lead placement.

AUTHORS

Ronald M. Harper, Ph.D.

Professor of Anatomy and Cell Biology

Department of Anatomy and Cell Biology

Rebecca K. Harper, M.A.

Staff Research Associate

Brain Research Institute

Christopher A. Richard, Ph.D.

Postgraduate Researcher

Department of Anatomy and Cell Biology

Robert B. Trelease, Ph.D.

Visiting Assistant Professor of Anatomy and Cell Biology

Department of Anatomy and Cell Biology

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University of California at Los Angeles

Los Angeles, CA 90024-1783

Robert R. Terreberry, Ph.D.

Visiting Assistant Professor of Biology

Department of Biology

Augustana College

Biology Building, Room 108

Rock Island, IL 81201

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Direct and Indirect Morphological

Markers of Cocaine Toxicity in the

Human Heart

Margaret E. Billingham

INTRODUCTION

There is increasing evidence that cocaine can have serious adverse effects on

the human heart. Angina, coronary artery spasm, arrhythmias, myocardial

infarction, endocarditis, coronary atherosclerosis, myocarditis, and sudden

death all have been reported in association with cocaine use. It is estimated

that almost 25 million Americans use cocaine with regularity, and approximately

1 million are addicted to this drug (Chokshi et al. 1989). The use of different

combinations of drugs and different routes of administration have further

increased the frequency and complications of cocaine. Cocaine also has

become a significant cause of heart disease and sudden death in athletes;

however, the cardiovascular changes in this group remain unexplained, and the

interaction between exercise and cocaine use is largely unstudied. This chapter

summarizes and examines the pathologic changes already ascribed to cocaine

abuse in the literature (table 1) under the following headings: (1) the pathologic

lesion, (2) the evidence or rationale that the lesion is indeed induced by cocaine

and the pitfalls of ascribing the lesions to cocaine, (3) the pathophysiological

explanation for the lesions, and (4) the possible consequences of cocaineinduced lesions.

TABLE 1. Pathologic lesions attributed to cocaine abuse in humans

Myocardial ischemia

“Catecholamine” microinfarcts

Fibrosis

Myocardial infarction

Myocarditis

Coronary artery “spasm”

Coronary arteriosclerosis

Cardiomyopathy (dilated, acute, and chronic)

Endocarditis

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MYOCARDIAL CONTRACTION BANDS

A. Lesion

Myocardial contraction bands associated with cocaine cardiotoxicity may have a

patchy or very focal distribution and are not seen in a global distribution as one

would expect with hypoxia. The lesions consist of dense hypereosinophilic

bands within the myocytes as seen on light microscopy stained with

hematoxylin and eosin (figure 1). In most cases, there is coagulative change in

the cytoplasm of the affected cell, and the nucleus may show pyknosls. In the

very focal lesions, actual myocyte necrosis also may be present (figure 2). On

electron microscopy, not only is there hypercontraction of the actin and myosin

but also swelling and redistribution of the intracellular mitochondria (figure 3).

Early changes in the myocyte are often highlighted by special stains such as

Masson’s trichrome or periodic acid-Schiff.

FIGURE 1. Human myocardium showing a typical, focal “cocaine effect” of a

hypereosinophilic myocyte (small arrow), contraction bands in

myocytes (long arrows), and coagulative necrosis of myocyte

cytoplasm (open arrow)

NOTE: Hematoxylin and eosin, magnification x 450.

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FIGURE 2. Human myocardium showing a typical, focal “cocaine effect” or

catecholamine effect of a single necrotic myocyte (arrow)

NOTE: Hematoxylin and eosin, magnification x 500.

B. Evidence and Pitfalls

We studied 30 cases of sudden death in cocaine abusers with a mean age of

33.9 years and compared them with a control group of 20 patients with sudden

death from sedative-hypnotic overdose who did not use cocaine (Tazelaar et al.

1987). A mean of 2.2 random sections was available from the myocardium of

the cocaine abusers and 3.2 random sections from each control patient. The

slides were examined and graded in a blinded fashion for the severity of

contraction band changes. There was a strong correlation between the blood

and urine levels of cocaine and the contraction bands in the myocardium

compared with those of the controls (table 2). These data suggest that cocaine

induces contraction bands in the myocardium.

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FIGURE 3. An electron micrograph of myocardium showing “contraction band

effect” (arrows) in a catecholamine-affected myocyte (M)

NOTE: Uranyl acetate, magnification x 4000.

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TABLE 2. Distribution of contraction band scores in cocaine addicts (sudden

deaths) vs. hypnotic-sedative overdose used as control groups

(sudden deaths)

Control Group Cocaine Group Contraction Band Score

(N=20) (N=30) (0-3+)

11

8

1

2

2

8

7

13

0

1+

2+

3+ (p<0.001)

SOURCE: Tazelaar et al. 1987.

On the other hand, contraction bands are not specific to cocaine. Many

experimental and clinical conditions also are associated with contraction band

changes in the myocardium. The nonspecificity of contraction bands has been

previously described in detail elsewhere (Karch and Billingham 1986). The

following list shows some other causes of myocardial contraction bands:

lschemia

Catecholamines

Hypopotassemia

Intracranial hemorrhage

Hypoxia, anoxia

Defibrillation

Steroids

Endomyocardial biopsy artifact

C. Pathophysiology

In the heart, only 30 percent of norepinephrine is metabolized by catechol-Omethyl transferase. After transmission of a nerve impulse, the bulk of

norepinephrine is transported back into the nerve terminal. Cocaine, however,

prevents norepinephrine reuptake, resulting in high local concentrations of

norepinephrine. The result of this is excessive beta receptor stimulation of

myocytes and the pathologic elevation of intracytosolic calcium, which results in

the formation of contraction bands or localized hypereosinophilia in a localized

area of the myocardium (figure 4). A second explanation may be the suggested

spasm of small vessels in the myocardium, causing “ischemia” or focal

microinfarcts.

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FIGURE 4. Human myocardium showing a focus of hypereosinophilic,

contracted myocytes (darker areas, arrows) typical of

catecholamine effect

NOTE: Hematoxylin and eosin, magnification x 300.

D. Consequences

The consequences of these changes in humans, which are also supported by

the high catecholamine blood levels in cocaine-intoxicated patients with chest

pain (Karch 1987), may proceed to frank myocardial ischemia and even

infarction. Later consequences are that ischemic areas may be a focus for the

development of re-entrant arrhythmias.

MYOCARDIAL FIBROSIS

A. Lesion

The lesion consists of small focal scars with ongoing reparative changes and

laying-down of early collagen. A later stage results in frank course fibrosis. In

cocaine abusers, the lesions tend to be focal, and even the well-developed

scars tend to be smaller than those observed in ischemic heart disease,

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particularly where they result from small vessel spasm. If an infarct has taken

place, then the resulting scar will be the same as in ischemic heart disease.

B. Evidence and Pitfalls

Several authors have noted fibrosis in the myocardium of autopsy tissue from

habitual cocaine users. In some cases, continuing destruction and healing of

the myocardium by fibrosis could explain a ‘cardiomyopathic” appearance of the

heart with ventricular dilatation and compensatory hypertrophy.

Fibrosis Is a nonspecific condition in the human myocardlum, with the possible

exception of its presence in young people (normally with little coronary disease),

which is more unusual. Fibrosis can be caused by several conditions in the

heart and by itself cannot be attributed to cocaine use.

C. Pathophysiology

There are several explanations for the presence of fibrosis in the heart in

cocaine abusers, and there is a possible relationship between them. Following

focal ischemia (contraction band necrosis), actual myocardial death may occur

which will result in replacement by fibrosis (figure 5). Lesions that develop from

microfocal fibrosis in the myocardium as a result of catecholamine-induced

lesions in pheochromocytoma are well known. They result eventually in the

development of a cardiomyopathic state with larger lesions of fibrosis (figure 8).

Myocardlal fibrosis also may result from coronary artery spasm or coronary

atherosclerosis since there are published reports of both conditions in cocaine

cardiotoxicity.

D. Consequences

Fibrosis, unless very focal, eventually can cause compensatory hypertrophy of

the myocardium and a general reduction in contractile efficiency of the

myocardium. Even focal scars can result in re-entrant arrhythmias such as is

seen in right ventricular arrhythmogenic dysplasia.

MYOCARDITIS

A. Lesions

Cellular infiltrates have been reported in the myocardium of cocaine abusers by

several researchers (Isner et al. 1980; Virmani et al. 1987; lsner et al. 1985).

The significance of these infiltrates in cocaine toxicity is not clear, but initial

studies suggest that they may result in focal myocardial necrosis and thus be

208
FIGURE 5. Panel A: focal ischemia due to cocaine in human myocardium;

panel B: focal scar or fibrosis resulting from lesion similar to

panel A

NOTE: Hematoxylin and eosin; magnification panel A=x 350, panel B=x 100.

209
FIGURE 6. Panel A: myocardium from a rat pheochromocytoma model with

typical early fibrosis in which fibroblast nuclei still can be seen

(arrows); panel B: resultant fibrous tissue (darker areas and

arrows) in the same model as panel A

NOTE: Masson’s trichrome, magnification x 250.

210
classified as a true myocarditis conforming to the Dallas criteria (Aretz et al.

1986). Eosinophilic myocardial infiltrates also have been described in

association with cocaine (Isner et al. 1980); however, these are more likely to

be the result of a hypersensitivity reaction that can be caused by several

unrelated agents. A hypersensitivity reaction to cocaine, or to drugs taken with

It, is also a possibility. The inflammatory lesions described are usually those of

a monomorphous infiltrate of lymphocytes; however, small focal lesions with

mixed infiltrates also have been seen that are similar to those produced by

catecholamine effect (figure 7).

FIGURE 7. Human myocardium showing focal myocarditis (short arrows point

to inflammatory cells) with myocyte necrosis (long arrows)

NOTE: Masson’s trichrome, magnification x 500.

B. Evidence and Pitfalls

The evidence of myocarditis in cocaine abusers rests in the fact that many

different researchers and observers have observed myocarditis in cocaine

abusers. The descriptions, however, do not conform to a definite pattern, and

both focal and diffuse patterns have been described as well as eosinophilic

211
rather than lymphocytic infiltrates. In some cases, the observers have not seen

the association of the infiltrates with actual myocyte damage.

The pitfalls in ascribing myocarditis to cocaine abuse is that cocaine use can

cause myocyte damage in a variety of ways and that the infiltrate may indeed

be a result of myocyte damage rather than true myocarditis.

C. Pathophysiology

Many of the pathophysiologic mechanisms of cocaine (e.g., catecholamine

effect) can cause focal lymphocytic infiltrates or focal myocarditis, which is in

fact a secondary phenomenon rather than a primary one caused by cocaine.

The myocarditis seen in cocaine abusers may be a true viral-related

lymphocytic myocarditis acquired in the debilitated state of a drug abuser and

not a primary effect of cocaine. Also, the eosinophilic infiltrate described may

be a hypersensitivity reaction due to contaminants of the cocaine rather than to

the drug itself. Until reliable experimental data with controls are available, it is

probably unwise to ascribe myocarditis to be the effect of cocaine per se.

D. Consequences

The primary consequences of myocarditis in cocaine abusers is the enhanced

probability of arrhythmias, particularly if the myocarditis involves the conducting

system of the patient. True myocarditis may result in a large flabby myocardium

with compromise of the ventricular function and may result in heart failure. The

long-term effects of a healed myocarditis are thought to result in a dilated

cardiomyopathy resulting in severe congestive heart failure.

CORONARY ARTERY CHANGES

A. Lesion

Vascular changes in cocaine abusers can be divided into reports of arterial

spasm and reports of epicardial coronary artery narrowing.

There are reports that cocaine can cause myocardial infarction in patients

without previous cardiovascular disease. It has been postulated that coronary

artery spasm may occur as a result of the sympathomimetic effect of cocaine or

even a direct effect on the smooth muscle of the coronary artery vessels (Factor

and Cho 1985).

Other reports describe narrowing of epicardial coronary arteries by

atherosclerotic plaque in cocaine abusers. Many of these patients die

212
suddenly, and some have had frank myocardial infarction. Patients with

preexisting coronary artery disease are also more prone to myocardial ischemia

from cocaine abuse. It appears that the incidence of coronary atherosclerosis

with significant epicardial coronary narrowing is more common in cocaine users

than in the normal population of the same age group (Bressler et al. 1990). In

some cases, there is superimposed thrombus. Virmani and associates

described two cocaine addicts with severe coronary atherosclerosis and a 23-

year-old woman who had an occlusive platelet thrombus in the left anterior

descending coronary artery (Virmani et al. 1988). Simpson and Edwards (1986)

described a 23-year-old male cocaine addict who died suddenly and was found

to have chronic coronary obstruction due to nonatherosclerotic concentric

intimal proliferation of smooth muscle cells.

B. Evidence and Pitfalls

At present the evidence that there is coronary artery spasm with the use of

cocaine is due to reports of fatal arrhythmia or myocardial infarction immediately

following the taking of cocaine. Work by Karch has demonstrated a rise In

catecholamine levels In patients with chest pain who have recently taken

cocaine (Karch 1987). Whether cocaine acts on endothelial factors or acts

directly on coronary vascular smooth muscle is not yet known (Van Houtte and

Shimokawa 1989).

Coronary artery disease, however, is a nonspecific finding and although the

studies described above are in fairly young patients in whom it is unusual to

have coronary artery disease, it is now known that there is an increasing

incidence of coronary disease in younger subjects. In several cardiac

transplantation cases, the hearts of young, apparently heart disease-free

donors frequently have shown significant but unexpected coronary artery

lesions. To be sure that cocaine indeed induces atherosclerotic coronary

disease, a reliable control study is necessary (so far this has not been shown in

animal studies either).

C. Pathophysiology

Coronary artery spasm may occur as a result of sympathomimetic effect of

cocaine or even a direct effect on the smooth muscle of the vessels as is

thought to occur in conditions such as pheochromocytoma. Whether cocaine is

acting on the endothelial factors or by direct action on coronary vascular smooth

muscle is not yet known.

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D. Consequences

The consequences of coronary artery disease, whether by spasm or an

increase in coronary artery atherosclerosis, may be thrombosis and occlusion of

the vessels with consequent ischemia or infarct of the myocardium. This also

may play a part in some of the sudden deaths attributed to cocaine use,

particularly in athletes whose hypertrophied myocardium may be more

susceptible.

CARDIOMYOPATHY

A. Lesion

There are a few reported cases of cocaine-induced cardiomyopathy. At

Stanford, we have seen at least three cases of dilated cardiomyopathy

diagnosed hemodynamically and clinically with a very strong history of cocaine

abuse. All three patients came to cardiac transplantation. The lesions in two of

these patients showed more focal lymphocytic infiltrates and less myocyte

hypertrophy than is normally seen in end-stage cardiomyopathy. However, the

size of the heart and the ventricular dilatation were the same as for idiopathic

cardiomyopathy. The cocaine abusers had a different pattern of fibrosis from

that normally seen in end-stage cardiomyopathy, in that the fibrous scars

tended to be smaller and more focal. The number of cases is too small at this

point to clearly define these lesions.

B. Evidence and Pitfalls

There is some evidence that cocaine use may result in acute cardiac dilatation;

however, it seems to result in a characteristic dilated cardiomyopathy in the

chronic abuser.

It is not clear whether these patients develop idiopathic cardiomyopathy as a

result of cocaine abuse or whether they are patients with idiopathic

cardiomyopathy who happen to be cocaine abusers. At this stage, there is little

evidence that shows cocaine can cause a cardiomyopathy of the dilated type.

C. Pathophysiology

The pathophysiological explanations of cocaine-induced dilated cardiomyopathy

is the same as that for the development of cardiomyopathy in

pheochromocytoma (Rosenbaum et al. 1987). The mechanism of

catecholamine effect is the same in both.

214
D. Consequences

The consequences of dilated cardiomyopathy with a low ejection fraction is a

marked congestive heart failure and possibly even death due to poor ventricular

contractility.

ENDOCARDITIS

A. Lesion

The lesion of endocarditis on the heart valves is similar to those in other

conditions. Grossly, the lesions of infective endocarditis are vegetations, small

flat adherent nodules to large friable masses, containing microorganisms

occasionally extending to the chordae. Microscopically, vegetations consist of

fibrin, platelets, and neutrophils at the bases. The underlying valve may be

eroded depending on the organism involved. In the case of self-administered

drugs, the lesions are usually on the right side of the heart, particularly the

tricuspid valve (figures 8 and 9). A recent study suggests that there is an

increased risk for endocarditis in intravenous (IV) cocaine drug abusers

(Chambers et al. 1987). Although endocarditis is well known as a complication

of IV drug use, this study suggests an increased risk involving cocaine abusers.

The lesions manifest themselves as endocarditis either in the acute or the

chronic stage on the tricuspid valve. Patients with bioprosthetic valves from

previous endocarditls (a common situation in IV drug users) are even more at

risk in the setting of cocaine addiction (figure 9). It has been suggested that

because cocaine is not “cooked” to dissolve it before injection, infection from

primary sites of bacteremia in the skin is more common in IV cocaine users.

B. Evidence and Pitfalls

One of the pitfalls of suggesting that endocarditis is due to cocaine use Is that

cocaine abusers also use other IV drugs. Illicit IV drug use often will result in

bacterial endocarditis. The evidence that endocarditis occurs more in cocaine

abusers is slight at this time and based on only one study.

C. Pathophysiology

The use of contaminated IV needles or contaminated material injected

intravenously by drug abusers may result in fungal, bacterial, or even foreign

body contaminants, which may lodge on the endothelium of the tricuspid valves

or other areas in the heart. It is known that foreign body and infectious

granulomas can occur in the lungs of self-administering IV drug abusers.

215
FIGURE 8. Panel A: human endocarditis valve v with a flat adherent

vegetation containing gram-positive organisms (arrow panel B)

NOTE: Panel A=hematoxylin and eosin, magnification x 50; panel B=gram

stain, magnification x 400.

218
FIGURE 9. Explanted bioprosthetic (porcine) heterograft valve only 6 months

after implantation in a drug addict

NOTE: Magnification x 2.5.

D. Consequences

The consequences of bacterial endocarditis are embolization from the lesions

with resultant lung infarcts or lung abscesses and even myocardial septicemia.

If the tricuspid valve is eroded sufficiently from endocarditis, it will become

incompetent or even stenotic.

CONCLUSIONS

Both definite and equivocal pathologic lesions due to cocaine cardiotoxicity are

now emerging as pathological entities in humans. None of the lesions are

217
specific, and in some cases the association is only circumstantial. It appears

that not only are there diverse types of lesions associated with cocaine use

such as those described above but also that the mechanisms for the production

of these lesions are quite varied. In most cases, there exists a plausible

clinicopathologic correlation to associate the various lesions with cocaine

abuse. The magnitude of the problem is unknown, and the temporal and dose

relationships to cocaine are still unclear and anecdotal; it is also unclear

whether some of the lesions are reversible. Estimates are not feasible without a

better understanding of how cocaine affects the cardiovascular system. It is

first necessary to establish definitely the different mechanisms of cocaine

cardiotoxicity; only then can a rational and effective therapy be applied to those

who have symptoms from cocaine abuse. Further studies and observations by

pathologists will assist in corroborating the presence of different lesions that

have been attributed to cocaine.

REFERENCES

Aretz, H.T.; Billingham, M.E.; Edwards, W.D.; Factor, S.M.; Fallon, J.T.;

Fenoglio, J.J., Jr.; Olsen, E.G.J.; and Schoen, F.J. Myocarditis: A

histopathologic definition and classification. Am Cardiovasc Pathol 1(1):3-14,

1986.

Bressler, F.A.; Malekzadeh, S.; and Roberts, W.C. Quantitative analysis of

amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol

65:303-308, 1990.

Chambers, H.F.; Morris, D.L.; Tauber, M.G.; and Modin, G. Cocaine use and

the risk for endocarditis in intravenous drug users. Ann Intern Med 106:833-

838, 1987.

Chokshi, S.K.; Rongione, A.J.; Miller, G.; and Isner, J.M. Cocaine and

cardiovascular disease. The Leading Edge: Cardiology 3:1-8, 1989.

Factor, S.M., and Cho, S. Smooth muscle contraction bands in the media of

coronary arteries: A postmortem marker of antimorten coronary spasm?

J Am Coll Cardiol 6(8):1329-1337, 1985.

Isner, J.M.; Estes, N.A.M.; Thompson, P.D.; Constanzo-Nordin, M.R.;

Subramanian, R.; Miller, G.; Katsas, G.; Sweeney, K.; and Sturner, W. Acute

cardiac events temporally-related to cocaine abuse. N Engl J Med 315:1438-

1443, 1980.

Isner, J.M.; Estes, N.A.M.; Thompson, P.D.; Nordin, M.R.; Subramanian, R.;

Miller, G.; Katsas, G.; Sweeney, K.; and Sturner, W. Cardiac consequences

of cocaine: Premature myocardial infarction, ventricular tachyarrhythmias,

myocarditis and sudden death. Circulation 72(Suppl 3]:111-415, 1985.

Karch, S.B. Serum catecholamine levels and cocaine-intoxicated patients with

cardiac symptoms. (Abstract.) Ann Emerg Med 16:481, 1987.

218
Karch, S.B., and Billingham, M.E. Contraction bands revisited. Hum Pathol

17:9-13, 1986.

Rosenbaum, J.S.; Billingham, M.E.; Ginsburg, R.; Tsujimoto, G.; Lurie, K.; and

Hoffman, B. Cardiomyopathy in a rat model of pheochromocytoma:

Morphologic and functional alterations. J Pharmacol Exp Ther 241:354-360,

1987.

Simpson, R.W., and Edwards, W.D. Pathogenesis of cocaine-induced ischemic

heart disease. Arch Pathol Lab Med 110:479-484, 1986.

Tazelaar, H.D.; Karch, S.B.; Stephens, B.G.; and Billingham, M.E. Cocaine and

the heart. Hum Pathol 18(2):195-199, 1987.

Van Houtte, P.M., and Shimokawa, H. Endothelial-derived relaxing factor and

coronary vasospasm. Circulation 80:1-9, 1989.

Virmani, R.; Robinowitz, M.; and Smialek, J.E. Cocaine-associated deaths:

Absence of coronary thrombosis and a high incidence of myocarditis. Lab

Invest 56(1):83a, 1987.

Virmani, R.; Robinowitz, M.; Smialek, J.E.; and Smyth, D.F. Cardiovascular

effects of cocaine: An autopsy study of 40 patients. Am Heart J 115:1068-

1076, 1988.

ACKNOWLEDGMENT

Steven Karch, M.D., assisted with the compilation of the data.

AUTHOR

Margaret E. Billingham, F.R.C. Path.

Professor of Pathology

Department of Cardiac-Pathology

Stanford University Medical School

300 Pasteur Drive, Room L215

Stanford, CA 94305

219
Cocaine-Associated Cardiovascular

Disease: Clinical and Pathological

Aspects

Renu Virmani

INTRODUCTION

Since pre-Columbian times, South American native peoples have ingested

cocaine as a stimulant by chewing coca leaves (Karch 1989). Subsequent

generations have discovered the "high” of cocaine’s psychologic stimulation and

have developed new ways to process and ingest cocaine to increase and

augment the intensity of the drug’s psychological effects. Initially, the use of

cocaine was promoted as a safe *high” however, with the increasing morbidity

and death associated with cocaine abuse, it is imperative to learn the

mechanisms involved with the toxic effects of cocaine (Gawin and Ellinwood

1988).

EPIDEMIOLOGY

Contemporary cocaine abuse is epidemic. In September 1987 the National

Institute on Drug Abuse reported that there were 5,000 new cocaine users daily

(Kozel and Adams 1986). Twenty-two million Americans have used cocaine at

least once: there are 6 million regular users and 0.2 to 1 million compulsive

users (Kozel and Adams 1986). Among persons 25 to 30 years of age, almost

40 percent have tried cocaine at least once (Gawin and Ellinwood 1988).

Although the annual prevalence of cocaine use among high school students

peaked during 1985 and 1986 at 13.1 percent and 12.7 percent, respectively, it

decreased to 10.3 percent in 1987, possibly as a result of adverse publicity

about the dangers of cocaine abuse (Kozel and Adams 1986; Barnes 1988)

and, in particular, the deaths of well-known athletes (Virmani et al. 1988). In the

past 20 years, there has been a 300-percent increase in emergency room visits

for cocaine-related conditions such as myocardial infarction, stroke, and

seizures as well as for possible adverse effects to unborn fetuses (Kozel and

Adams 1986). Cocaine deaths rose from 195 in 1981 to 580 in 1985. Many of

these deaths are attributed to cocaine’s adverse effects on the cardiovascular

system.

220
Cocaine's Effects on the Heart

The effects of cocaine on the cardiovascular system are numerous. They

include the following:

Functional effects

—Hypertension and tachycardia

—Increased coronary vascular resistance

—Arrhythmias

-Sudden death

Pathologic effects

—Myocardial infarction with/without coronary atherosclerosis

-Coronary atherosclerosis and/or intimal smooth muscle cell proliferation

-Platelet aggregation

—Myocarditis

Catecholamines

-Small vessel spasm

—Contraction band necrosis

Catecholamines

—Rupture of the ascending aorta

Cocaine may induce myocardial ischemia by increasing the work of the heart

and increasing the demand for oxygen by elevating the blood pressure and

heart rate. It also could be caused by decreasing the blood supply in the

epicardial coronary arteries in the presence of fixed obstruction by

atherosclerosis (figure 1) and/or by inducing vasoconstriction of intramyocardial

coronary arteries and/or increased platelet aggregation and thrombosis (Cregler

and Mark 1986).

Myocardial lschemia

Since 1982 acute myocardial infarction, with or without thrombosis, has been

related temporally to cocaine use in at least 52 patients clinically or at autopsy

(Virmani et al. 1988; Cregler and Mark 1986; lsner et al. 1986). Of these, the

majority had little or no fixed underlying coronary atherosclerosis by

angiography. Coronary thrombosis was suspected or present in at least nine

patients studied angiographlcally or at autopsy (Virmani et al. 1988; Cregler and

Mark 1986; lsner et al. 1986; Zimmerman et al. 1987).

Mittleman and Wetli (1987) recently reported 24 cases (ages 20 to 71 years) of

sudden death associated with cocaine abuse; 15 of these individuals had

severe coronary atherosclerosis; 10 had coronary stenosis with 70- to 85-

221
FIGURE 1. Pathologic findings from the autopsy examination of young adults dying with cocaine detected in body

fluids. A platelet thrombus in the left anterior descending coronary artery overlying an eccentric

atherosclerotic plaque that occupied 40 percent of cross-sectional luminal area in a 23-year-old woman

with a history of chemical abuse of freebase cocaine (crack) and marijuana B. Eccentric atherosclerotic

plaque with pultaceons debris and a fibrous cap (H&Ex40). C. High-power view of platelet thrombus

(H&Ex 300).
percent cross-sectional luminal narrowing; and 5 had 90-percent luminal

narrowing. Complete thrombotic occlusion occurred in 3 patients; healed

myocardial infarction was present in 10 patients; and 2 had acute myocardial

infarction. Therefore, cocaine also may play a contributory role in natural death

in the presence of severe underlying coronary atherosclerosis, either through

increase in oxygen demand or through induction of coronary spasm.

Etiology. Myocardial ischemia is a well-recognized sequela of coronary

atherosclerosis and accounts for the majority of patients with myocardiai

infarction. However, myocardial infarction with normal coronary arteries is

uncommon, with a reported prevalence of 1 to 3 percent (Zimmerman et al.

1987). The pathophysiology of myocardial ischemia may be coronary spasm

and thrombosis. The majority of the coronary arteriograms of patients with

cocaine abuse and myocardial infarction have demonstrated normal or minor

irregularities (isner et al. 1986; Zimmerman et al. 1987). This raises the

possibility that cocaine induces coronary spasm and thrombosis with

subsequent lysis of the thrombus. Coronary artery spasm In humans has been

shown angiographically to be localized at sites with insignificant coronary

atherosclerosis (Maseri et al. 1978). We and others hypothesize that cocaine

induces vasoconstriction through the sympathomimetic action of cocaine, which

may result in compromised blood flow and endothelial disruption at sites of

atherosclerosis. Endothelial disruption at these sites initiates a cycle of platelet

aggregation (Simpson and Edwards 1986; Hueter 1987). Platelets release

prostaglandins, which may further cause vasoconstriction. Coronary artery

spasm and thrombosis have been demonstrated in a 29-year-old man with

angiographically normal coronary arteries with cocaine abuse (Zimmerman et

al. 1987).

Platelet Aggregation. The alpha-adrenergic properties of cocaine increase

platelet aggregation, which may precipitate thrombi in the coronary artery in the

presence or absence of fixed stenosis. In vitro studies of platelet function have

shown that cocaine enhances both thromboxane production and the

aggregating response of platelets, which may be mediated by calclummembrane binding and calcium influx (Virmani et al. 1988; Hueter 1987). The

vasoconstrictor properties of thromboxane A2

 on medium- and small-size

arteries may contribute further to coronary vasoconstriction. In young adults

who abuse cocaine, increased platelet aggregability may lead to fibromuscular

intimal proliferation through the release of platelet-derived growth factor and

nonatherosclerotic coronary luminal narrowing (Zimmerman et al. 1987; Hueter

1987).

223
Myocarditis

Several studies have reported the presence of lymphocytic and eosinophilic

myocarditis in patients with detectable cocaine or cocaine metabolites in body

fluids (Virmani et al. 1988; lsner et al. 1986; Simpson and Edwards 1986; Karch

and Billingham 1988). Myocarditis was diagnosed histologically using the

Dallas criteria, defined as a mononuclear infiltrate with or without eosinophilic

leukocytes of five or more cells per focus and myocyte necrosis manifested

either by hypereosinophilic myocytes, coagulation necrosis, or scalloped

margins of myocytes. These criteria document a noxious effect on the

myocardium but do not identify an etiologic agent or agents.

We reviewed the files of the medical examiner of the State of Maryland and

identified 40 deaths associated with cocaine abuse (Virmani et al. 1988).

Patients were divided into two groups: group 1—natural deaths, 31 patients

(mean age 38±5 years, 22 males and 9 females) in whom death was attributed

directly to cocaine toxicity (cocaine blood levels 5.3±8.1 mg/L)—and group 2—

homicide deaths, 9 patients (mean age 33±8 years; 7 males and 2 females) in

whom presence of cocaine was not the cause of death (0.3±0.3 mg/L). Four of

the 31 natural death patients had lymphocytic myocarditis; of the 9 homicide

deaths, 2 had lymphocytic myocarditis (figure 2, panel A), and 2 had

lymphocytic and eosinophilic myocarditis (figure 2, panel B). The foci of

myocarditis were focal and sparse with equal distribution in both the right and

left ventricles.

Etiology. The cause of myocarditis in these patients is unknown but may be

infectious agents such as bacteria, fungi, or viral inclusions, although none were

found. The myocarditis may be due to indirect induction of myocyte necrosis

with secondary inflammatory infiltrate elicited by cocaine-evoked inhibitions of

norepinephrine reuptake. On the other hand, cocaine may cause

vasoconstriction of small intramyocardial coronary arteries with a resultant

increase in coronary vascular resistance, which has been documented in

humans and animals (Lange et al. 1989; Hale et al. 1989; Bedotto et al. 1988).

These factors may lead to isolated myocyte necrosis, secondary to ischemia.

Also, the action of cocaine on endogenous catecholamines may affect

lymphocytic activity. An increase in natural killer-cell activity has been reported

with the use of intravenous cocaine (Dyke et al. 1986). Natural killer cells may

cause myocyte death with inflammatory infiltrate. However, the precise

mechanism of myocarditis remains unknown.

Eosinophilic myocarditis has been associated with hypersensitivity myocarditis

secondary to an adverse reaction to various drugs. Hypersensitivity myocarditis

usually is located in the natural tissue planes within the myocardium and

consists of lymphocytes and eosinophils in the absence of myocyte necrosis.

224
FIGURE 2. A Myocardium of a 37-year-old female chronic cocaine abuser and homicide victim. Note focus of

lymphocytic myocarditis surrounding a necrotic myocyte (H&E x 630). B. Myocardium of a 27-year-old

chronic cocaine abuser and drug-related homicide victim. Note focus of eosinophilic (arrowhead) and

lymphocytic myocarditis with myocyte necrosis (H&E x 750).
The two cases of eosinophilic myocarditis In Maryland may represent a

hypersensitivity reaction to cocaine, its metabolites, or other unidentified

chemicals that may be contaminants.

Contraction Band Necrosis

Contraction band necrosis is defined as the hypercontraction of some

sarcomeres, interspersed with other sarcomeres that are torn apart within the

myocytes. Under light microscopy, these appear as dense, amorphous areas of

hypercontracted myofilaments alternating with lighter areas with decreased

amounts of myofilaments (figure 3) incapable of further contraction (Karch and

Billingham 1988). Contraction bands may be due to elevated levels of

norepinephrine triggered by cocaine, which may Induce intramural coronary

artery spasm or directly stimulate hypercontraction of myocardial cells via an

influx of calcium ions (Karch and Billingham 1988).

Tazelaar and colleagues (1987) reported a 93-percent incidence of contraction

band necrosis in the myocardium of cocaine-associated deaths in contrast to an

incidence of 45 percent in deaths associated with sedative-hypnotic overdose.

They attributed the presence of contraction band necrosis to cocaine-induced

catecholamlne myocardial injury. Norepinephrine and epinephrine levels have

been found to be elevated in cocaine users who present to the emergency room

(Karch and Billingham 1988). Similar lesions of contraction band necrosis have

been shown to occur in experimental animals with elevated serum

catecholamlne levels (Gopinath et al. 1978). However, in our recent study

(Virmani et al. 1988) of 40 patients In whom cocaine or Its metabolites were

detected in body fluids, contraction band necrosis occurred in only 10 patients

(25 percent). The incidence of contraction band necrosis was higher in the

study’s sudden traumatic death control group (41 percent) (Virmani et al. 1988).

The lower incidence in this study is difficult to explain but may reflect differences

in the population studied or in cocaine preparations, contaminants and

adjuvants in the drugs of abuse, rate of drug delivery, and/or chronicity of drug

abuse (Virmani et al. 1988).

Aortic Rupture

To our knowledge, only one patient, a 45-year-old man, has been reported to

have died of aortic dissection and rupture after smoking freebase cocaine off

and on for several hours before death (Barth et al. 1986). The dissection, which

involved the ascending aorta 2 cm above the sinotubular junction, suggests that

a marked elevation of blood pressure must have occurred after cocaine

ingestion, which has been clinically documented to occur in humans and

animals (Lange et al. 1989; Hale et al. 1989; Bedotto et al. 1988; Dyke et al.

1986; Barth et al. 1986).

226
FIGURE 3. A 22-year-old man with sudden onset of seizure who died while

snorting cocaine. Note contraction band necrosis with

hyperwntracted eosinophilic bands alternating with light areas

within myocytes (H&E x 300).

SUMMARY

With regard to cardiac findings in cocaine abuse, at autopsy the vast majority of

patients dying with cocaine toxicity have either no pathologic change in the

heart or only minimal changes that could not account for the patient’s death.

The second most frequent finding is underlying, mild-to-moderate coronary

atherosclerosis, with or without coronary thrombosis. There may be acute or

healed myocardial infarction or a sudden cardiac death without myocardial

changes of ischemia. A high incidence of contraction band necrosis has been

reported in the absence of coronary artery disease and may cause a sudden

arrhythmic death. Myocarditis also has been described in a few cases as either

lymphocytic or lymphocytic and eosinophilic infiltrate in the presence of myocyte

necrosis. Usually, the foci are sparse and not always associated with

contraction band necrosis. The underlying mechanisms are thought to be either

227
direct effects of norepinephrIne on myocytes or through vasospasm of

resistance vessels and secondary myocardial ischemia. Cocaine rarely has

been associated with aortic dissection, which is probably a result of cocaine’s

hypertensive effects.

REFERENCES

Barnes, D.M. Drugs: Running the numbers. Science 240:1729-1731, 1988.

Barth, C.W.; Bray, M.; and Roberts, WC. Rupture of the ascending aorta

during cocaine intoxication. Am J Cardiol 57(6):496, 1986.

Bedotto, J.B.; Lee, R.W.; Lancaster, L.D.; Olajos, M.; and Goldman, S. Cocaine

and cardiovascular function in dogs: Effects on heart and peripheral

circulation. J Am Coll Cardiol 1:1337-1342, 1988.

Cregler, L.L., and Mark, H. Special report. Medical complications of cocaine

abuse. N Engl J Med 315:1495-1500, 1986.

Dyke, C.V.; Stesin, A.; Jones, R.; Chuntharapal, A.; and Seaman, W. Cocaine

increases natural killer-cell activity. J ClIn West 77:1387-1390, 1986.

Gawin, F.H., and Ellinwood, E.H., Jr. Cocaine and other stimulants: Actions,

abuse, and treatment. N Engl J Med 318:1173-1182, 1988.

Goplnath, C.; Thuring, J.; and Zayed, I. Isoprenaline-induced myocardial

necrosis in dogs. Br J Exp Path 59:148-157, 1978.

Hale, S.L.; Alker, K.J.; Razkalla, S.; Figures, G.T.; and Kloner, R.A. Adverse

effects of cocaine on cardiovascular dynamics, myocardial blood flow, and

coronary artery diameter in experimental models. Am Heart J 118:927-933,

1989.

Hueter, DC. Cardiovascular effects of cocaine. JAMA 257:979-980, 1987.

Isner, J.M.; Ester, M. III; Thompson, P.D.; Costanzo-Nordin, M.R.;

Subramanian, R.; Miller, G.; Katsas, G.; Sweeney, K.; and Sturner, W.Q.

Acute cardiac events temporally related to cocaine abuse. N Engl J Med

315:1438-1443, 1986.

Karch, S.B. The history of cocaine toxicity. Hum Pathol 20:1037-1039, 1989.

Karch, S.B., and Billingham, M.E. The pathology and etiology of cocaineinduced heart disease. Arch Pathol Lab Med 112:225-230, 1988.

Kozel, N.J., and Adams, E.H. Epidemiology of drug abuse: An overview.

Science 234:970-974, 1986.

Lange, R.A.; Cigarroa, R.G.; Yancy, C.W.; Willard, J.E.; Popma, J.J.; Sills,

M.N.; McBride, W.; Kim, A.S.; and Hillis, L.D. Cocaine-induced coronary

artery vasoconstrlctlon. N Engl J Med 321:1557-1562, 1989.

Maseri, A.: L’Abbate, A.; Baroldi, G.; Chierchia, S.; Marzilli, M.; Baleestra, A.M.;

Severi, S.; Parodi, O.; Biagini, A.: Distante, A.; and Pesola, A. Coronary

vessel spasm as a possible cause of myocardial infarction. A conclusion

derived from the study of "preinfarctlon” angina. N Engl J Med 299:1271-

1277, 1978.

228
Mittleman, R.E., and Wetli, C.V. Cocaine and sudden “natural death.”

J Forensic Sci 32:11-19, 1987.

Simpson, R.W., and Edwards, W.D. Pathogenesis of cocaine-induced ischemic

heart disease. Autopsy flndings in a 21 -year-old man. Arch Pathol Lab Med

110:479-484, 1986.

Tazelaar, H.; Karch, S.B.; Stephens, B.G.; and Billingham, M.E. Cocaine and

the heart, Hum Pahol 18:195-199, 1987.

Virmani, R.; Robinowitz, M.; Smialek, J.E.; and Smyth, D.F. Cardiovascular

effects of cocaine: An autopsy study of 40 patients, Am Heath J 115:1068-

1076,1988.

Zimmerman, F.H.; Gustafson, G.M.; and Kemp, H.G., Jr. Recurrent myocardial

infarction associated with cocaine abuse in a young man with normal

coronary arteries: Evidence for coronary artery spasm culminating in

thrombosis. J Am Coll Cardiol 9:964-968, 1987.

AUTHOR

Renu Virmani, M.D.

Chairman

Cardiovascular Pathology

Armed Forces Institute of Pathology

Washington, DC 20306-6000

229
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47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION

STRATEGIES. Thomas J. Glynn, Ph.D.; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds. A RAUS Review Report.

GPO out of stock NCADI out of stock

NTIS PB #85-159663/AS $31

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING

BEHAVIOR. John Grabowski, Ph.D., and Catherine Bell, M.S., eds.

GPO out of stock NCADI out of stock

NTIS PB #84-145184/AS $23

50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF

ABUSE. John Grabowski, Ph.D., ed.

GPO Stock #017-024-01214-9 $4 NTIS PB #85-150381/AS $23

232
51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS,

AND PROSPECTS. Frank M. Tims, Ph.D., ed.

GPO out of stock NTIS PB #85-150365/AS $23

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND

ABUSE LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D., eds.

GPO out of stock NTIS PB #85-150373/AS $23

53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION. John

Grabowskl, Ph.D., and Sharon M. Hall, Ph.D., eds.

GPO out of stock NCADI out of stock

NTIS PB #89-123186/AS $23

54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm.

Sharp, Ph.D., ed.

GPO out of stock NCADI out of stock

NTIS PB #89-103279/AS $39

55 PROBLEMS OF DRUG DEPENDENCE, 1984: PROCEEDINGS OF THE

46TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO out of stock NCADI out of stock

NTIS PB #89-123194/AS $45

58 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION.

Coryl LaRue Jones, Ph.D., and Robert J. Battjes, D.S.W., eds.

GPO Stock #017-024-01250-5 $6.50 NTIS PB #89-123160/AS $31

57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING

CURRENT CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D.; Nicholas

J. Kozel, M.S.; and Louise G. Richards, Ph.D., eds.

GPO out of stock NTIS PB #88-248083/AS $23

58 PROGRESS IN THE DEVELOPMENT OF COST-EFFECTIVE

TREATMENT FOR DRUG ABUSERS. Rebecca S. Ashery, D.S.W., ed.

GPO out of stock NTIS PB #89-125017/AS $23

59 CURRENT RESEARCH ON THE CONSEQUENCES OF MATERNAL

DRUG ABUSE. Theodore M. Pinkert, M.D., J.D., ed.

GPO out of stock NTIS PB #89-125025/AS $23

233
60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora

Chiang, Ph.D., and Charles C. Lee, Ph.D., eds.

GPO out of stock NTIS PB #89-124564/AS $23

61 COCAINE USE IN AMERICA: EPIDEMIOLOGIC AND CLINICAL

PERSPECTIVES. Nicholas J. Kozel, M.S., and Edgar H. Adams, M.S., eds.

GPO out of stock NTIS PB #89-131866/AS $31

62 NEUROSCIENCE METHODS IN DRUG ABUSE RESEARCH. Roger M.

Brown, Ph.D.; David P. Friedman, Ph.D.; and Yuth Nimit, Ph.D., eds.

GPO out of stock NCADI out of stock

NTIS PB #89-130660/AS $23

63 PREVENTION RESEARCH: DETERRING DRUG ABUSE AMONG

CHILDREN AND ADOLESCENTS. Catherine S. Bell, M.S., and Robert Battjes,

D.S.W., eds.

GPO out of stock NTIS PB #89-103287/AS $31

64 PHENCYCLIDINE: AN UPDATE. Doris H. Clouet, Ph.D., ed.

GPO out of stock NTIS PB #89-131858/AS $31

65 WOMEN AND DRUGS: A NEW ERA FOR RESEARCH. Barbara A. Ray,

Ph.D., and Monique C. Braude, Ph.D., eds.

GPO Stock #017-024-01283-1 33.50 NTIS PB #89-130637/AS $23

68 GENETIC AND BIOLOGICAL MARKERS IN DRUG ABUSE AND

ALCOHOLISM. Monique C. Braude, Ph.D., and Helen M. Chao, Ph.D., eds.

GPO out of stock NCADI out of stock

NTIS PB #89-134423/AS $23

68 STRATEGIES FOR RESEARCH ON THE INTERACTIONS OF DRUGS

OF ABUSE. Monique C. Braude, Ph.D., and Harold M. Ginzburg, M.D., J.D.,

M.P.H., eds.

GPO out of stock NCADI out of stock

NTIS PB #89-134936/AS $31

69 OPIOID PEPTIDES: MEDICINAL CHEMISTRY. Rao S. Rapaka, Ph.D.;

Gene Barnett, Ph.D.; and Richard L. Hawks, Ph.D., eds.

GPO out of stock NTIS PB #89-158422/AS $39

70 OPIOID PEPTIDES: MOLECULAR PHARMACOLOGY, BIOSYNTHESIS,

AND ANALYSIS. Rao S. Rapaka, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO out of stock NTIS PB #89-158430/AS $45

234
71 OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M.

Brown, Ph.D.; Doris H. Clouet, Ph.D.; and David P. Friedman, Ph.D., eds.

GPO out of stock NTIS PB #89-151955/AS $31

72 RELAPSE AND RECOVERY IN DRUG ABUSE. Frank M. Tims, Ph.D.,

and Carl G. Leukefeld, D.S.W., eds.

GPO Stock #017-024-01302-1 $8 NTIS PB #89-151963/AS $31

73 URINE TESTING FOR DRUGS OF ABUSE. Richard L. Hawks, Ph.D., and

C. Nora Chiang, Ph.D., eds.

GPO Stock #017-024-01313-7 83.75 NTIS PB #89-151971/AS $23

74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE.

Stephen I. Szara, M.D., D.Sc., ed.

GPO Stock #017-024-01314-5 $3.75 NTIS PB #89-151989/AS $23

75 PROGRESS IN OPIOID RESEARCH. PROCEEDINGS OF THE 1986

INTERNATIONAL NARCOTICS RESEARCH CONFERENCE. John W.

Holaday, Ph.D.; Ping-Yee Law, Ph.D.; and Albert Hen, M.D., eds.

GPO out of stock NCADI out of stock

Not available from NTIS

78 PROBLEMS OF DRUG DEPENDENCE, 1986: PROCEEDINGS OF THE

48TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO out of stock NCADI out of stock

NTIS PB #88-208111/AS $53

77 ADOLESCENT DRUG ABUSE: ANALYSES OF TREATMENT

RESEARCH. Elizabeth R. Rahdert, Ph.D., and John Grabowski, Ph.D., eds.

GPO Stock #017-024-01348-0 $4 NCADI out of stock

NTIS PB #89-125488/AS $23

78 THE ROLE OF NEUROPLASTICITY IN THE RESPONSE TO DRUGS.

David P. Friedman, Ph.D., and Doris H. Clouet, Ph.D., eds.

GPO out of stock NTIS PB #88-245683/AS $31

79 STRUCTURE-ACTIVITY RELATIONSHIPS OF THE CANNABINOIDS.

Rao S. Rapaka, Ph.D., and Alexandros Makriyannis, Ph.D., eds.

GPO out of stock NTIS PB #89-109201/AS $31

235
80 NEEDLE SHARING AMONG INTRAVENOUS DRUG ABUSERS:

NATIONAL AND INTERNATIONAL PERSPECTIVES. Robert J. Battjes,

D.S.W., and Roy W. Pickens, Ph.D., eds.

GPO out of stock NTIS PB #88-236138/AS $31

81 PROBLEMS OF DRUG DEPENDENCE, 1987: PROCEEDINGS OF THE

49TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01354-4 $17 NTIS PB #89-109227/AS

Contact NTIS for price

82 OPIOIDS IN THE HIPPOCAMPUS. Jacqueline F. McGinty, Ph.D., and

David P. Friedman, Ph.D., eds.

GPO out of stock NTIS PB #88-245691/AS $23

83 HEALTH HAZARDS OF NITRITE INHALANTS. Harry W. Haverkos, M.D.,

and John A. Dougherty, Ph.D., eds.

GPO out of stock NTIS PB #89-125496/AS $23

84 LEARNING FACTORS IN SUBSTANCE ABUSE. Barbara A. Ray, Ph.D.,

ed.

GPO Stock #017-024-01353-8 $6 NTIS PB #89-125504/AS $31

85 EPIDEMIOLOGY OF INHALANT ABUSE: AN UPDATE. Raquel A. Crider,

Ph.D., and Beatrice A. Rouse, Ph.D., eds.

GPO Stock #017-024-01380-9 $5.50 NTIS PB #89-123178/AS $31

86 COMPULSORY TREATMENT OF DRUG ABUSE: RESEARCH AND

CLINICAL PRACTICE. Carl G. Leukefeld, D.S.W., and Frank M. Tims, Ph.D.,

eds.

GPO Stock #017-024-01352-8 $7.50 NTIS PB #89-151997/AS $31

87 OPIOID PEPTIDES: AN UPDATE. Rao S. Rapaka, Ph.D., and Bhola N.

Dhawan, M.D., eds.

GPO Stock #017-024-01366-8 $7 NTIS PB #89-158430/AS $45

88 MECHANISMS OF COCAINE ABUSE AND TOXICITY. Doris H. Clouet,

Ph.D.; Khursheed Asghar, Ph.D.; and Roger M. Brown, Ph.D., eds.

GPO Stock #017-024-01359-5 $11 NTIS PB #89-125512/AS $39

89 BIOLOGICAL VULNERABILTY TO DRUG ABUSE. Roy W. Pickens,

Ph.D., and Dace S. Svikis, B.A., eds.

GPO Stock #017-022-01054-2 $5 NTIS PB #89-125520/AS $23

238
90 PROBLEMS OF DRUG DEPENDENCE, 1988: PROCEEDINGS OF THE

50TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01362-5 $17

91 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

GPO Stock #017-024-01384-6 $10 NTIS PB #90-147257/AS $39

92 TESTING FOR ABUSE LIABILITY OF DRUGS IN HUMANS. Marian W.

Fischman, Ph.D., and Nancy K. Mello, Ph.D., eds.

GPO Stock #017-024-01379-0 $12 NTIS PB #90-148933/AS $45

93 AIDS AND INTRAVENOUS DRUG USE: FUTURE DIRECTIONS FOR

COMMUNITY-BASED PREVENTION RESEARCH. C.G. Leukefeld, D.S.W.;

R.J. Battjes, D.S.W.; and Z. Amsel, D.Sc., eds.

GPO Stock #017-024-01388-9 $10 NTIS PB #90-148941/AS $39

94 PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE AND

RELATED DESIGNER DRUGS. Khursheed Asghar, Ph.D., and Errol De

Souza, Ph.D., eds.

GPO Stock #017-024-01388-2 $11 NTIS PB #90-148958/AS $39

95 PROBLEMS OF DRUG DEPENDENCE, 1989: PROCEEDINGS OF THE

51 ST ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01399-4 $21 NTIS PB #90-237880/AS $87

96 DRUGS OF ABUSE: CHEMISTRY, PHARMACOLOGY, IMMUNOLOGY,

AND AIDS. Phuong Thi Kim Pham, Ph.D., and Kenner Rice, Ph.D., eds.

GPO Stock #017-024-01403-8 $8 NTIS PB #90-237678/AS $31

97 NEUROBIOLOGY OF DRUG ABUSE: LEARNING AND MEMORY. Lynda

Erinoff, Ph.D., ed.

GPO Stock #017-024-01404-4 $8 NTIS PB #90-237686/AS $31

98 THE COLLECTION AND INTERPRETATION OF DATA FROM HIDDEN

POPULATIONS. Elizabeth Y. Lambert, M.S., ed.

GPO Stock #017-024-01407-9 $4.75 NTIS PB #90-237694/AS $23

99 RESEARCH FINDINGS ON SMOKING OF ABUSED SUBSTANCES.

C. Nora Chiang, Ph.D., and Richard L. Hawks, Ph.D. eds.

GPO Stock #017-024-01412-5 $5

237
100 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

VOL. Ii. Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

101 RESIDUAL EFFECTS OF ABUSED DRUGS ON BEHAVIOR. John W.

Spencer, Ph.D., and John J. Boren, Ph.D., eds.

GPO Stock #017-024-01426-5 $8

102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., and Lynda Erinoff,

Ph.D., eds.

GPO Stock #017-024-01425-7 $8

103 DRUGS AND VIOLENCE: CAUSES, CORRELATES, AND

CONSEQUENCES. Mario De La Rosa, Ph.D.; Elizabeth Y. Lambert, M.S.;

and Bernard Gropper, Ph.D., eds.

GPO Stock #017-024-01427-3 $9

104 PSYCHOTHERAPY AND COUNSELING IN THE TREATMENT OF

DRUG ABUSE. Lisa Simon Onken, Ph.D., and Jack D. Blaine, M.D., eds.

GPO Stock #017-024-01429-0 $4

105 PROBLEMS OF DRUG DEPENDENCE, 1990: PROCEEDINGS OF THE

52ND ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

106 IMPROVING DRUG ABUSE TREATMENT. Roy W. Pickens, Ph.D.; Carl

O. Leukefeld, D.S.W.; and Charles R. Schuster, Ph.D., eds.

107 DRUG ABUSE PREVENTION INTERVENTION RESEARCH:

METHODOLOGICAL ISSUES. Carl G. Leukefeld, D.S.W., and William J.

Bukoski, Ph.D., eds.

238
DHHS Publication No. (ADM) 91-1767

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1991