AMERICANSOCIETY OF
HYPERTENSION
September 1999
Volume 3
Issue 3CURRENT CONCEPTS IN

Hypertension
SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT FROM PFIZER, INC.

EDITORIAL BOARD
Editor-in-Chief
Myron H. Weinberger, MD
Hypertension Research Center
Indiana University School of Medicine

Page 3

Stevo Julius, MD, ScD
The University of Michigan Medical Center
Robert A. Kloner, MD, PhD
The Heart Institute
University of Southern California
Laurence R. Krakoff, MD
Mount Sinai School of Medicine
Englewood Hospital & Medical CenterFranz H. Messerli, MD, FACC, FACP
Ochsner Clinic
Michael A. Weber, MD
The Brookdale Hospital Medical Center

IN
THIS
ISSUE
Page 4

Managing Editor
Patrice N. Light, PharmD
Postgraduate Institute for Medicine

Page 2
Editor’s Comments
News From Framingham:
The AASK Study andInsulin Resistance—
Is it Due to No NO?
Myron H. Weinberger, MD

The American Society of Hypertension
515 Madison Avenue, Suite 1212 • New York, NY • 10022

The Effect of Age andHypertension on Systolic,
Diastolic, Mean, andPulse Pressure: The
Framingham Heart Study
Stanley S. Franklin, MD
William Gustin IV, BS
Nathan Wong, PhD
Michael Weber, MD
Martin Larson, ScD
William Kannel, MD
Daniel Levy, MD

The Rationale for the
African-American Studyof Kidney Disease andHypertension
Kenneth A. Jamerson, MD

Page 6Hypertension and Insulin
Resistance: Is Defective
Nitric Oxide Production
One Missing Link?
Helmut Steinberg, MD

NONPROFIT ORG.
U.S. POSTAGEPAID
PERMIT NO. 489
DENVER, COEditor’s Comments
NEWS FROM FRAMINGHAM: THE AASK STUDY AND INSULIN RESISTANCE—IS IT DUE TO NO NO?
Myron H. Weinberger, MD

Editor-in-Chief
Professor of Medicine
Director, Hypertension ResearchCenterIndiana University School of
Medicine
Indianapolis, Indiana

This issue of Current Concepts in Hypertension continues the description of ongoing clinical
trials and outcome studies by bringing new information from the oldest of the observational
studies in cardiovascular disease now in its 51st year (the Framingham Study). Dr. Stanley Franklin
summarizes the most recent findings from Framingham regarding the age-related changes insystolic and diastolic pressure and provides insight into the importance of pulse pressure, an
important predictor of cardiovascular events associated with aging.
Dr. Kenneth Jamerson provides descriptive information regarding one of the most recent intervention trials designed to examine the causes and possible approaches to prevention of end-stage
renal disease in African-American hypertensives (the AASK study). The background and rationale for the trial are discussed, along with the experimental design. The results of this important
study should be available in the next 3 years.
Dr. Helmut Steinberg provides additional information regarding the possible role of nitric oxide production in the pathophysiology of insulin resistance, a commonly encounteredabnormality in hypertensive subjects. These observations may help explain the association between insulin resistance and blood pressure.

The American Society ofHypertension

515 Madison Avenue, Suite 1212
New York, NY 10022
212-644-0650
Published by
Postgraduate Institute for
Medicine
304 Inverness Way South, Suite 265
Englewood, CO 80112
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Copyright © 1999
All rights reserved.
The opinions or views expressed in thearticles are those of the authors and do
not necessarily reflect the opinions or
recommendations of the publisher,
the sponsor, the American Journalof Hypertension, or the American
Society of Hypertension.
2

THE EFFECT OF AGE AND HYPERTENSION ON SYSTOLIC, DIASTOLIC, MEAN, AND PULSE
PRESSURE: THE FRAMINGHAM HEART STUDY

P

revious studies have shown a progressive increase in bloodpressure (BP) with aging in industrialized societies, beginning inchildhood and progressing throughout adulthood. We attempted tocharacterize these age-related changes in BP in both normotensive
and untreated hypertensive subjects in a population-based cohort fromthe original Framingham Heart Study and to infer underlying
hemodynamic mechanisms.1

Stanley Franklin, MD; William
In this study, the standard cuff
Gustin IV, BS; Nathan Wong,pressures showed a leveling off
PhD; and Michael Weber, MD
of MAP values in both normoUniversity of California at Irvine
tensive and hypertensive groups
Irvine, California
after age 50 to 60. In the hyperMartin Larson, ScD; William
tensive groups MAP actually
Kannel, MD; and Daniel Levy, MD
decreased after the seventh or
Framingham Study Investigatorseighth decade (Fig. 1). MAP, derived from the standard equation
and using brachial artery readings, is thought to approximate PVR in young subjects when cardiac
output is not elevated. The fall in DBP secondary to the increase inlarge artery stiffness explains why the MAP equation grossly underestimates PVR after 50 years of age.

There was a linear rise in systolic blood pressure (SBP) from age 30
through 84 years and a concurrent increase in diastolic blood pressure (DBP) and mean arterial pressure (MAP) until about 50 years ofage (Fig. 1, red line). After age 50 to 60 years, DBP declined, pulsepressure (PP) rose steeply, and MAP leveled off while SBP continued
to show a linear increase throughout the geriatric years.

Table 1 The Effect of Systolic Blood Pressure on

The almost parallel rise in SBP, DBP, and MAP up to age 50 can best
be explained by an increase in peripheral vascular resistance (PVR).2
The reduction in DBP has been attributed to “burned out” diastolichypertension but this decrease in DBP was noted in both normotensive and untreated hypertensive subjects. Furthermore, of those
hypertensives whose SBPs were >140 mm Hg, only a third had antecedent DBP of >90 mm Hg prior to the onset of declining DBP
values. Two thirds of the hypertensive population had maximum DBP
of <90 mm Hg throughout their entire course. Similarly, the conceptof “selective survivorship” has been postulated as a cause of the latedecline in DBP. However, this was not consistent with persistence ofthe late fall in DBP after removal of all deaths and patients with nonfatal myocardial infarction (MI) or congestive heart failure (CHF)from the study sample (Fig. 1, blue line). A further hypothesis, namely
an age-related decrease in cardiac output as the cause for the late fallin DBP, is inconsistent with the late rise in SBP. Similarly, increase in
PP is not due to bradycardia for there was a step-wise increase in heart
rate with rising SBP (Table 1). The most plausible explanation for theBP pattern from age 50 onward, therefore, is an increase in large
artery stiffness caused by intrinsic structural abnormalities.2,3 With
age-related stiffening of the aorta, there is decreased elasticity andgreater peripheral runoff of stroke volume during systole. With lessblood remaining in the aorta at the beginning of diastole and withdiminished elastic recoil, DBP decreases and the diastolic decay curve
becomes steeper.3

Heart Rate: The Framingham Heart StudySBP Group

Mean BP(mm Hg)Heart Ratea(beats/min)Standard
Error

Group
Differences(P value)1

111/70

72.7

±0.64

0.0001

2

129/77

75.0

±0.44

0.0001

3

148/83

77.5

±0.57

0.0001

4

173/90

80.5

±0.78

0.0001

Heart rates were determined at baseline examination in normotensive anduntreated hypertensive subjects by systolic blood pressure groupings. Group 1
had <120 mm Hg; group 2, 120 to 139 mm Hg; group 3, 140 to 159 mm Hg;
group 4, >160 mm Hg. The study cohort consisted of 2036 subjects (890 men
and 1146 women). BP = blood pressure, SBP = systolic blood pressure.
a
All heart rates were age and sex adjusted.
Data derived from Franklin SS, et al. Circulation 1997;96:308-315.

The Framingham findings also support the concept of an interaction
between aging and hypertension in the progressive fall of DBP and riseof SBP. Subjects with mean baseline BPs of 111/70 (Fig. 2, group 1)
had no rise in PP and only a minimal increase in MAP from age 30 to49 years. Nevertheless, this group of normotensive subjects showed asignificant rise in PP and fall in DBP after age 60 years, presumablycaused by an increase in large artery stiffness secondary to aging. In
contrast, subjects with baseline mean BPs of 173/90 (Fig. 2, group 4)

Figure 1 Arterial Pressure Components by Age
Groups Determined at Indexed Examination
Mean ArterialGroup 3 SBP 140-159

Pulse

115

100
3
2

95
90

1

85

78

Diastolic Pressure (mm Hg)

4

105

Pulse Pressure (mm Hg)

3

68

2

58

1

48

30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

Age

Systolic

95
90
85
4

80
75

3
2
1

70
65
Age

Age

175
4

165
155

3

145

2

135

1

125
115
105

30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

38

80

30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

MAP (mm Hg)

Diastolic
4110

All Subjects
Deaths, MI, and CHF Excluded

Group 4 SBP 160+

30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

Group 2 SBP 120-139

Systolic Pressure (mm Hg)

Group 1 SBP <120

Age

Arterial pressure components by age (group averaged data for all subjects and with deaths, MI, and CHF excluded) with averaged blood pressure levels from allavailable data from each subject within 5-year age intervals by SBP groupings 1 through 4. The red line represents the entire study cohort (2036 subjects) and theblue line the study cohort with deaths, nonfatal MI, and CHF excluded (1353 subjects).
Reproduced with permission of Lippincott Williams & Wilkins, from Franklin SS, et al. Circulation 1997;96:308-315.

3

THE RATIONALE FOR THE AFRICAN-AMERICAN STUDY OF KIDNEY DISEASE AND
HYPERTENSIONT

he pathophysiology of hypertensive nephrosclerosis and its
ultimate sequela, hypertensive end-stage renal disease (HTN
ESRD), constitutes a greater disease burden for African Americans.
A current estimate, based on epidemiologic studies, is that 7 million
African Americans have essential hypertension.1 The United States
Renal Data System 1993 Annual Report2 indicated an incidence of
12,000 African-American ESRD patients in 1990, of which 4880
had hypertension as the primary cause of kidney failure. This
represents a population attributable risk of 40% compared to 23%
in whites. Between 1983 and 1990, the incidence of HTN ESRD
increased by 500% in African Americans. Total enrollment in the
ESRD program is expected to reach 250,000 by the year 2000.3

at 21 centers in the United
Kenneth A. Jamerson, MD
Division of Hypertension
States. Approximately 1100
Department of Internal Medicine
men and women, aged 18 to
University of Michigan Medical School
70 years with a diagnosis of hyAnn Arbor, Michigan
pertension and renal impairment (iothalamate clearance 20
to 65 mL/min) were recruited.
The basis of the evaluation for two levels of BP control arises, inpart, from observations in the Modification of Diet in Renal Disease (MDRD) study. African Americans in this study randomized
to the low BP target (<92 MAP) had a decline in glomerular filtration rate (GFR) that was about half the rate observed in participants randomized to the usual BP group (MAP 102 to 108mm Hg). This result inferred that targeting a DBP of 75 mm Hg
was more protective of renal function than the more traditionaltarget DBP of 90 mm Hg. However, because there were so few
African Americans in the MDRD study, it could not be determined whether lower BP was truly beneficial. Subjects are followed

The African-American Study of Kidney Disease and Hypertension (AASK) is a clinical trial sponsored by the National Institutesof Health. It is designed to compare the effects of two levels of BP
control (MAP 102 to 107 and <92 mm Hg) and 3 different antihypertensive drug regimens (angiotensin-converting enzyme inhibitor [ACEI], calcium channel blocker [CCB], or β-blocker) on
renal function in African Americans. The study is being conducted

Continued on page 5.

THE EFFECT OF AGE AND HYPERTENSION ON SYSTOLIC, DIASTOLIC, MEAN, AND PULSE PRESSURE: THE FRAMINGHAM HEART STUDY
Figure 2 The Effect of Age and Hypertension on

may be sex differences in arterial stiffening, with young women having
more compliant vessels. With the onset of menopause this difference
may be lost, with a resulting acceleration in arterial stiffening.

Pulse Pressure and Mean Arterial Pressure
Mean Arterial Pressure
115
110

1

50
40

MAP mm Hg

60

The clinical implications that can be derived from this study are that,after the sixth decade of life: (1) increasing PP and decreasing DBP aresurrogate measurements for large artery stiffness; (2) large artery stiffness rather than vascular resistance becomes the dominant hemodynamic factor in both normotensive and hypertensive subjects; and (3)hypertension, left untreated, may accelerate the rate of development oflarge artery stiffness. This, in turn, can perpetuate a vicious cycle ofaccelerated hypertension and further increases in large artery stiffness.

4

105
100
95
90

1

85

30
30
-3
5
35
-4
0
40
-4
5
45
-5
0
50
-5
5
55
-6
0
60
-6
5
65
-7
0
70
-7
5

80
30
-3
5
35
-4
0
40
-4
5
45
-5
0
50
-5
5
55
-6
0
60
-6
5
65
-7
0
70
-7
5

PP mm Hg

70

Age

Age

Arterial pressure components by age. Averaged pulse pressure levels and meanarterial pressure levels from all available data are from each subject within 5-year
age intervals by systolic blood pressure (SBP) groupings. Group 1 had a meanbaseline BP of 111/70; Group 4 had a mean baseline BP of 173/90.

References
1. Circulation 1997,96:308–315.
2. Berne M, Levy MN. Cardiovascular Physiology.
St. Louis: Mosby Year Book. 1992.

Adapted from Franklin SS. Circulation 1997;96:308-315.

showed a steeper rise in PP and a steeper fall in DBP after age 60 than
was observed in group 1 subjects. This divergent rather than parallel
tracking pattern observed in all 4 SBP groups has been referred to as thehorse-racing effect, there being a close correlation between the speed of
the horse and its position in the race. These findings suggest a linkage
between hypertension left untreated and subsequent acceleration of large
artery stiffness. Although increased PVR may initiate essential hypertension, acceleration of large artery stiffness is the driving force leading
to the steeper rise of SBP after age 50 in the hypertensive groups 3 and4 as compared to normotensive groups 1 and 2 (Fig. 1).

3. Nichols WW, O’Rourke MF. McDonald’s
bloodflow in arteries, 4th ed. London:
Arnold, Hodder Headling Group, 1998.

Figure 3 Arterial Pressure Components Averaged by

Age and Sex
Groups Determined at Indexed Examination
Group 1 SBP <120 (Males)Group 1 SBP <120 (Females)Group 4 SBP >160 (Males)Group 4 SBP >160 (Females)

Systolic

DiastolicSystolic Pressure mm Hg

175

Age-related BP changes were generally similar in both sexes but, as
noted previously, our findings showed young women had lower BPs
than similarly aged men (Fig. 3). These differences gradually narrowed
and eventually reversed beyond age 60 years. Sex differences in BP weremore marked in hypertensive subjects. These findings suggest there

165

4

155
145
135
125

1

115
30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

105
Age

Diastolic Pressure mm Hg

4

95
90
85

4

80
75
70

1

65
30
-3
35 4
-3
40 9
-4
45 4
-4
50 9
-5
55 4
-5
60 9
-6
65 4
-6
70 9
-7
75 4
-7
80 9
-8
4

Pulse Pressure
80

Age

Averaged blood pressure levels from all available data for each subject with
5-year age intervals by SBP groupings 1 versus 4.
Reproduced with permission of Lippincott Williams & Wilkins, from Franklin SS, et al. Circulation 1997;96:308-315.

4

THE RATIONALE FOR THE AFRICAN-AMERICAN STUDY OF KIDNEY DISEASE AND
HYPERTENSION (Continued from page 4)
Table 2 Baseline Characteristics of AASK Participantsfor 4 years. The study endpoints are a 50% decline in GFR ortime to renal failure, defined as dialysis.

(n=1094)
Baseline Characteristics

There is substantial evidence that the treatment of hypertension
may not adequately affect the progression to renal failure. Subjects
with hypertension and impaired renal function may not improveand even progress despite normalization of BP.4-6 While clinical trials and epidemiology surveys define hypertension by the application of discrete categorical specifications (DBP ≥90 mm Hg), thedeleterious effect of elevated BP on the kidneys and other target
organs is a continuous risk function. There are inherent problems
in this arbitrary categorization of a continuously distributed attributeor characteristic. One such problem of immediate relevance is whatlevel of BP in an individual (member of a population) is to be considered optimal with respect to the prevention of renal parenchyma
disease progression and, simultaneously, safe with respect to adequate
perfusion of other vital vascular beds?

Age

54.5 years

Blood pressure

150/95 mm Hg

Gender (M/F)

60%/40%Weight

90 kg
46 mL/min/1.73 m2

GFR
Years of hypertension

14 years

Antihypertensive drugs at entry (N)2.4

Smokers

31%

With private health insurance

40%

With education <grade 12

40%

Employed

36%

Income at poverty level50%

fer from one or more methodologic deficiencies relating to inadequate sample size, inappropriate patient selection criteria, relatively
short follow-up period, defective control group or lack of control,
and the utilization of suboptimal measures of renal function.21 An
important limitation of the available clinical studies is inclusion of
few or no African Americans, the subgroup with the highest incidence of hypertensive renal parenchymal disease. Bauer et al.22 reported a clinical trial of 23 patients with one of the longest follow-up
periods. After 3 years of followup, patients with essential hypertension and moderately impaired renal function (inulin clearance <80
cc/min) treated with enalapril showed a 33% higher inulin clearance compared to placebo. Sunderrajan et al.23 demonstrated a mean
62% improvement in GFR at 16 months in a group of 18 patientswith pretreatment GFR ≥80 cc/min/1.73m2.

An analysis of the Multiple Risk Factor Intervention Trial (MRFIT)
cohort1 indicates that DBP <95 mm Hg is associated with a positive reciprocal creatinine slope (+0.0012 dL/mg/yr) compared topatients with DBP ≥95 mm Hg which was associated with a negative reciprocal creatinine slope (-0.0013 dL/mg/yr) after 6 years offollowup. This beneficial effect of lower DBP was observed in whites
but not in African-American participants in the MRFIT cohort. At
10.5 years of followup, there was no significant reduction in renalmortality in either African Americans or whites, nor was there any
relationship between baseline level of creatinine and mortality.7
The concept of a renoprotective antihypertensive regimen (e.g., theselective ability of specific antihypertensive agents to reverse, restitute or prevent the pathophysiologic progression of hypertensive
renal disease when compared to an equally effective alternative antihypertensive regimen) offers a potentially useful therapeutic strategy to ameliorate hypertensive renal disease. This consideration isparticularly relevant to African Americans in whom effective control of systemic hypertension may not translate into protection fromrenal parenchyma disease.

The AASK study began with a 2-year pilot phase to examine thefeasibility of a long-term clinical trial. The first 98 subjects underwent renal biopsy. This demonstrated that the pathologic feature of
hypertensive nephropathy was not unique in African Americans.
With the initiation of the full scale trial, 21 clinical centers enrolled
1100 subjects. The baseline characteristics of the group can be foundin Table 2. There is currently greater than 93% compliance with allclinic visits, 75% pill taking compliance, and dramatic changes in BP(average BP during followup is 137/84 mm Hg). The study is progressing in a manner such that there will be adequate power to answer
all study question. We anxiously anticipate the results in 2002.

A substantial body of evidence indicates two main classes of pharmacologic agents (ACEIs and some CCBs) may have renoprotective
effectiveness under experimental conditions.8,9 ACEIs have been
demonstrated to decrease postglomerular capillary resistance andnormalize glomerular capillary pressure, thus protecting the kidneyfrom the development of arteriolar nephrosclerosis.10,11 An additional nonrenin-mediated renoprotective effect of ACEIs may be
the enhancement of bradykinin and cellular vasodilatory prostaglandin biosynthesis.12 Experimental evidence also indicates CCBs
may protect the glomerular microcirculation from hypertensive injury by way of afferent arteriolar dilation and reduction of glomerular capillary pressure.l3,l4 These experimental evidences of therenoprotective effects of ACEIs and CCBs have been supported byseveral clinical trials that have demonstrated a reversal, stabilization, or slowing of the progression of renal function in diverse hypertensive patient populations with varying degrees of renal
insufficiency.l3,l5-20 Unfortunately, most of these clinical studies suf-

References
1.
2.
3.
4.
5.
6.
7.

JAMA 1992;268:3085–3091.
Am J Kidney Dis 1993;22 Suppl 2:17–20.
Arch Intern Med 1991;151:1280–1287.
Circulation 1969;40:893–904.
Ann Intern Med 1980;93:676–681.
Am J Med 1964;36:795–804.
Workshop on the Biology of Kidney
Disease and Hypertension in Blacks,
National Institute of Diabetes andDigestive and Kidney Diseases.
December 11-13, 1991.
8. Am J Kidney Dis 1991;27:85–88.
9. Am J Hypertens 1989;2:173S–178S.
10. Am J Kidney Dis 1991;27:89–93.

5

11. Hypertension 1987;10:140–151.
12. Kidney Int 1984;25:969–983.
13. J Clin Invest 1986;77:1993–2000.
14. Kidney Int 1987;31:752–759.
15 Am J Hypertens 1992;5:423–430.
16. Hypertension 1986;8:238–242.
17. Hypertension 1988;11:452–456.
18. Am J Kidney Dis 1987;10:446–451.
19. Am J Nephrol 1988;8:285–290.
20. Am J Kidney Dis 1989;13:120–126.
21. Hypertension 1989;13 Suppl D:I-66–
I-68.
22. Arch Intern Med 1987;147:1397–1400.
23. Am J Hypertens 1987;114:383–388.

HYPERTENSION AND INSULIN RESISTANCE:IS DEFECTIVE NITRIC OXIDE PRODUCTION ONE MISSING LINK?

B

oth essential hypertension and insulin resistance increase therisk of cardiovascular disease. The prevalence of each conditionis ~30% and still rising. Insulin resistance is defined as decreased
rates of glucose uptake in response to insulin. Insulin resistance isassociated with a number of metabolic abnormalities such as
dyslipidemia and hypertension. For the last decade it has been acknowledged that both conditions occur together more commonly
than predicted by chance, suggesting a mechanistic relationship between the conditions. Whether insulin resistance causes hypertension and/or whether hypertension induces insulin resistance isunknown. Both scenarios are possible and not mutually exclusive.
In this short review, evidence will be presented that impaired endothelial function with decreased nitric oxide (NO) production may
be one link between insulin resistance and hypertension.

tion is blunted in insulin resisHelmut Steinberg, MD
Assistant Professor of Medicine
tant obese and Type II diabetic
Division of Endocrinology
subjects we hypothesized thatIndiana University School of
insulin resistance is associatedMedicinewith impaired endothelial funcIndianapolis, Indianation. In fact, the response to theendothelium-dependent vasodilator methacholine, but not
to the endothelium-independent vasodilator sodium nitroprusside,
was significantly reduced in the insulin resistant obese and diabetic
subjects.6 Moreover, Petrie and colleagues,7 using the NO synthaseinhibitor L-NMMA, showed that NO-dependent blood flow, a measure of endothelial NO production, correlated positively with insulin sensitivity. Taken together, these data indicate insulin resistanceis associated with impaired endothelial function and decreased NO
production rates.

NO is generated from L-arginine in a reaction catalyzed by the enzyme NO synthase which is expressed constitutively in the vascularendothelial cells. NO generation is modulated by shear stress and avariety of hormones such as insulin, estrogen, atrial natriuretic factor, epinephrine, bradykinin, and acetylcholine. NO diffuses throughthe subendothelial space to the vascular smooth muscle cell where
it activates the enzyme guanylate cyclase which increases levels of
cyclic GMP, ultimately resulting in vasorelaxation and increased local
flow. At the local level, this NO action will augment the supply of
substrate (i.e. insulin and glucose) that may result in increased
tissue metabolism. At the level of the whole body, this NO action
will lead to lower BP levels. Thus, it is conceivable that impaired
endothelial NO production may contribute to BP elevation andinsulin resistance.

Insulin mediated increments in skeletal muscle blood flow correlated positively with glucose uptake rates (insulin sensitivity) andinversely with resting BP.8 Therefore, it is not surprising that insulin
resistant hypertensive subjects exhibited decreased insulin mediatedvasodilation.9 However, not all forms of hypertension are associatedwith insulin resistance10 and it is not known whether these patients
exhibit impaired NO production. Importantly, BP elevation inducedby either norepinephrine11 or angiotensin II12 did not cause insulin
resistance. These data suggest that elevated BP, per se, may not be
sufficient to cause insulin resistance—especially when the NO system is left intact. On the other hand, inhibition of NO productionin the leg induced insulin resistance (decreased insulin-mediatedglucose uptake)13,14 and small increments in BP, and systemic inhibition of NO production in animals15 produced both insulin resistance and hypertension. These data suggest that impaired endothelial
function with decreased NO production may be necessary for thedevelopment insulin resistance accompanied by BP elevation.

Hypertension has been shown to display impaired blood flow increments in response to the endothelium-dependent vasodilator
acetylcholine.1 In contrast, the blood flow response to the NO donor sodium nitroprusside, which is endothelium independent, wasnormal suggesting that the observed defect was due to decreased
release of NO at the level of the vascular endothelium and not to
reduced NO action at the level of the vascular smooth muscle. This
notion was recently supported by Forte and colleagues2 who, usingsophisticated tracer techniques, demonstrated decreased total body
NO production rates in subjects with essential hypertension. Thus,
hypertension is associated with impaired endothelial function anddecreased NO production.

In summary, impaired endothelial function and decreased NO production is one abnormality shared by insulin resistance and essential hypertension. Given the multiple antiatherosclerotic actions ofNO, impaired NO production may not only explain the clusteringof hypertension and insulin resistance but also the macrovasculardisease observed with hypertension and with insulin resistance.

References
In 1990, Laakso and coworkers3 demonstrated that insulin increased
leg blood flow in a dosage dependent fashion. Furthermore, leg bloodflow increments and rates of glucose metabolism correlated positively
and strongly, suggesting that insulin’s metabolic and vascular effects
are coupled. Importantly, insulin’s stimulation of blood flow was
blunted in insulin resistant obese and Type II diabetic subjects. In
normal insulin-sensitive subjects, insulin-mediated vasodilation isaccompanied by increased sympathetic nervous system activity andincreased cardiac output with a small reduction in MAP, indicating
marked vasodilation at the level of the skeletal muscle vasculature.4

1.
2.
3.
4.
5.
6.
7.
8.

Our group was able to show that this insulin mediated vasodilation
depends on the release of NO.5 Because insulin-mediated vasodila6

N Engl J Med 1990;323:22–27.
Lancet 1997;349 (9055):837–842.
Diabetes 1992;41:1076–1083.
Am J Physiol 1993;265:E61–E67.
J Clin Invest 1994;94:1172–1179.
J Clin Invest 1996;97:2601–2610.
Circulation 1996;93: 1331–1333.
Hypertension 1993;21:129–135.

9. J Hypertens 1998;16:211–219.
10. Am J Hypertens 1992;5:26–28.
11. J Clin Invest 1994;93:2453–2462.
12. J Clin Invest 1993;92:720–726.
13. J Clin Invest 1995;96:786–792.
14. Am J Physiol 1996;271:E1067–E1072.
15. Am J Physiol 1995;269 (4 Pt 1):E709–
E715.