bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Liver Fractions on Myocardial Contractility
Authors: GREEN JACK PETER , NAHUM L. H.
Published: June 2012

Tyramine was crystallized and identified as one of the cardioactive materials in liver extract. Of many other compounds tested on the isolated papillary muscle of the cat, only methionine, ethionine, serotonin, heparin, testosterone, Menadione, and Dicoumarol showed activity.
Alterations in Central Blood Volume and Cardiac Output Induced by Positive Pressure Breathing and Counteracted by Metaraminol (Aramine)
Authors: BRAUNWALD E. , BINION J. T. , MORGAN W. L. , SARNOFF S. J. , Anderson. W.
Published: June 2012

High levels of positive pressure breathing in the dog resulted in substantial depression of central blood volume as well as cardiac output and arterial pressure. The administration of metaraminol elevated these lowered values while positive pressure breathing was maintained. The beneficial effects observed are thought to be attributable to this drug's influence on venous and arteriolar tone and myocardial contractility. The mechanism of the circulatory depression produced by positive pressure breathing is discussed.
A dynamic electrical record of the pathway of human His bundle activation from surface mapping.
Authors: Horan L G , Flowers N C , Sohi G S
Published: June 2012

Body surface potential maps of human His bundle activity have been difficult to product for two reasons: (1) The peak surface potentials are often less than 5 muv, and (2) the simultaneous atrial repolarization potentials frequently exceed 100 muv. We have therefore amplified surface signals 25 times the standard gain of 1000, and then removed by cross-correlation the static pattern of atrial repolarization for serial 1-msec maps of the P-R segment in five normal men. A consistent finding emerged: a positive anterior chest peak appeared 40 msec before QRS onset, and then-within 10 msec-spread out into a long, low transverse mound before disappearing in 5 more msec. The map data were analytically converted to serial electrical sources: the center of electrical activity moved first slightly down, then directly forward, before retracing its path and disappearing. The retrace and accompanying surface spread-out strongly suggests diverging dipolar sources. Thus the data fit a simple heart source which moves anteriorly and then breaks into two (right and left)-as expected from activation of the bundle of His and its bifurcation into left and right bundle branches.
Role of renal nerves, angiotensin II, and prostaglandins in the antinatriuretic response to acute hypercapnic acidosis in the dog.
Authors: Anderson R J , Henrich W L , Gross P A , Dillingham M A
Published: June 2012

Although clinical studies suggest that chronic hypercapnic acidosis may be associated with renal sodium retention, little information is available on the effect of acute hypercapnic acidosis on renal sodium excretion. We, therefore, increased PCO2 from 23 to 74 mm Hg in anesthetized dogs and observed a marked antinatriuresis as absolute sodium excretion (235 to 60 muEq/min, P less than 0.001) and fractional excretion of sodium (4.0 to 1.2 %, P less than 0.02) decreased significantly. This decrease in sodium excretion occurred independent of consistent changes in renal perfusion pressure, PO2, glomerular filtration rate, renal blood flow, extraction of P-aminohippuric acid, and filtration fraction. The antinatriuretic response to acute hypercapnic acidosis could be attenuated significantly by surgical renal denervation, intrarenal phenoxybenzamine, and by intrarenal infusion of 1-sarcosine,8-glycine angiotensin II. Administration of 10 mg/kg indomethacin enhanced the antinatriuretic response to hypercapnic acidosis in denervated kidneys. These results suggest that renal alpha-adrenergic nerves and the renal angiotensin system result in an antinatriuretic effect during acute hypercapnic acidosis. Renal prostaglandins or related substances may serve to attenuate this antinatriuretic response.
The effects of verapamil, quiescence, and cardioplegia on calcium exchange and mechanical function in ischemic rabbit myocardium.
Authors: Bourdillon P D , Poole-Wilson P A
Published: June 2012

The effects of verapamil (1 mg/liter, 2 x 10(-6) mol/liter), quiescence, and cardioplegia (K+ 16 mmol/liter, Mg2+ 16 mmol/liter) on calcium exchange and mechanical function during ischemia and reperfusion have been investigated in the rabbit interventricular septum at 32 degrees C. Calcium influx and efflux were recorded continuously with 47Ca2+ and 45Ca2+. After 60 minutes of total ischemia and reperfusion for 30 minutes, there was a net calcium gain of 4.9 mmol/kg dry tissue. Verapamil given before total ischemia reduced net calcium gain to 1.5 mmol/kg dry tissue (n = 5, P less than 0.03). When given only on reperfusion after total ischemia, or 10 minutes before reperfusion during low flow ischemia, verapamil did not affect calcium exchange. Cardioplegia begun 10 minutes before total ischemia reduced net calcium gain to 1.0 +/- 0.26 mmol/kg dry tissue (n = 6, P less than 0.001). Cardioplegia during the first 10 minutes of reperfusion, or lack of electrical stimulation during reperfusion, did not reduce calcium gain. Net calcium gain correlated with the maximum rise in resting tension and with the recovery of developed tension. In control experiments neither verapamil nor cardioplegia altered influx or efflux of slowly exchanging calcium. The cardioprotective effects of cardioplegia and the calcium channel blocker verapamil appear to be due to a reduction of myocardial work rather than to any specific direct action on calcium fluxes across the myocardial cell membrane.
Rate and rhythm dependency of propagation from normal myocardium to a Ba++, K+-induced slow response zone in rabbit left atrium.
Authors: Masuda M O , de Carvalho A P
Published: June 2012

Strips of rabbit atrium 2-3 mm wide and 10-12 mm long were used to study how normal propagating action potentials excite a region where slow responses are the only form of electrical activity. One end of the preparation was bathed in normal Tyrode's solution. The rest was exposed to Tyrode's solution with high K+ (12.7 mM) and Ba++ (1 mM) (TKBa solution). The normal end was electrically stimulated and activity was monitored extra- and intracellularly (3 M KCl microelectrodes) as it propagated into the TKBa-treated region. We observed that the slow response could be elicited optimally by the normal action potential only within a limited range of stimulation frequencies (from around 0.3 to 1 Hz). At higher frequencies, progressive "fatigue" of slow response was observed. At frequencies lower than this range, normal action potentials were unable to stimulate slow response. To clarify the mechanism under this behavior, slow responses were directly elicited by electrical stimulation of strips wholly bathed in TKBa. Rate dependency of slow response excitability was again observed. Conclusions are: slow response excitability is enhanced transiently at each stimulation; the enhanced excitability state subsides very slowly and may take as long as 10 seconds to disappear; the enhanced state is cumulative from cycle to cycle so that excitability increases with increasing frequencies of stimulation above 0.1 Hz; and high frequency block due to fatigue and block due to excitability depression at low frequency delimit an optimal frequency window for slow response excitation and conduction.
Differential baroreflex control of heart rate and vascular resistance in rabbits. Relative role of carotid, aortic, and cardiopulmonary baroreceptors.
Authors: Guo G B , Thames M D , Abboud F M
Published: June 2012

We assessed the relative roles of aortic (ABR), carotid sinus (CBR), and vagal cardiopulmonary baroreceptors in the reflex control of heart rate and vascular resistance during changes in arterial blood pressure. Injections of phenylephrine (PE) and nitroglycerin (NG) were given intravenously to anesthetized rabbits (chloralose-urethane). Reflex, heart rate responses were impaired significantly by denervation (X) of either CBR or ABR. In contrast, reflex vascular responses in the hindlimb (perfused at constant blood flow) were preserved except for a slight impairment of reflex vasoconstriction after ABRX. Vagotomy with intact CBR and ABR impaired only the reflex bradycardia. After vagotomy, neither CBRX nor ABRX altered significantly the reflex heart rate or vascular responses except, again, for an impairment of reflex vasoconstriction after ABRX. Combined CBRX and ABRX eliminated all reflex responses except for a small bradycardia and a biphasic change in perfusion pressure (constrictor-dilator) during PE. Vagotomy eliminated the bradycardia and the dilator phase; the constrictor phase persisted and was abolished by lumbar sympathectomy. The results indicate that (1) reflex control of heart rate may be impaired when reflex control of hindlimb resistance is preserved; thus reflex changes in heart rate may not be used as a reliable index of the integrity of arterial baroreceptor control of the total circulation; (2) one set of arterial baroreceptors does not compensate for the absence of the other with respect to activation of vagal neurons; in contrast, one set of baroreceptors compensates fully for the absence of the other with respect to inhibition of sympathetic neurons; (3) cardiopulmonary and other baroreceptors contribute minimally to reflex responses only during large PE-induced increases in arterial pressure.
Norepinephrine sensitivity and desensitization of cultured single vascular muscle cells.
Authors: Hermsmeyer K , Mason R
Published: June 2012

Isolated single vascular muscle cells were used for studies of the inherent norepinephrine sensitivity and the conditions important for detecting highest norepinephrine sensitivity. Rat vascular muscle cell contractions were quantitated from spontaneous contractions during pulse applications of the drugs, with a time course designed to simulate norepinephrine release in situ. Isolated vascular muscle cells showed a sensitivity to norepinephrine two orders of magnitude greater than those found from isolated intact blood vessels. Associated with the high sensitivity, there was a marked reduction in the response to a second application of norepinephrine or phenylephrine. The reduced second response appears to result from desensitization that is more pronounced in cells that have been exposed to only trace concentrations of catecholamines. These data appear to suggest that there might be continuous suppression of transmitter sensitivity that occurs as a result of transmitter exposure, and possibly cell-to-cell associations. Desensitization would at first severely limit the response to norepinephrine by reducing or eliminating the response to prolonged exposure or a second dose. Thereafter, a lessening of the desensitization process on continuous exposure to catecholamines would be the result, in part, of lowered sensitivity and, in part, of a smaller desensitization response. This process would continuously modulate norepinephrine sensitivity, based on the frequency and extent of stimulation, and we have called it the theory of physiological desensitization.
Low dose intrarenal infusions of PGE2, PGI2, and 6-keto-PGE1 vasodilate the in vivo rat kidney.
Authors: Jackson E K , Heidemann H T , Branch R A , Gerkens J F
Published: June 2012

The renal vascular effects of prostaglandin E2 (PGE2), 6-keto-PGE1, and PGI2 were investigated in indomethacin-pretreated rats. These prostanoids were infused directly into the left renal artery at rates ranging from 0.01 to 1.0 microgram/min, while renal blood flow and mean arterial blood pressure were constantly monitored. PGE2, 6-keto-PGE1, and PGI2 produced reductions in mean arterial blood pressure with threshold doses of 1.0, 0.3, and 0.03 microgram/min (P less than 0.01), respectively, and maximal vasodepressor responses of 18.9 +/- 4.3, 37.0 +/- 7.8, and 58.7 +/- 8.2 mm Hg (P less than 0.01), respectively. In addition, all three prostanoids caused a dose-related reduction in renal vascular resistance with a threshold dose of 0.01 microgram/min (P less than 0.05). The maximal reductions in renal vascular resistance were 2.59 +/- 0.52, 4.41 +/- 1.20, and 5.29 +/- 1.06 mm Hg/(ml per min) for PGE2, 6-keto-PGE1, and PGI2 (P less than 0.01), respectively. Whereas PGE2 an 6-keto-PGE1 produced dose-dependent increases in renal blood flow (maximal increases of 1.5 +/- 0.3 and 1.0 +/- 0.3 ml/min, respectively (P less than 0.01), PGI2 nonsignificantly increased renal blood flow at low doses and decreased renal blood flow at higher infusion rates (P less than 0.01). These data indicate that the in vivo rat kidney, similar to the kidneys of other species, is vasodilated by low doses of PGE2, PGI2, and 6-keto-PGE1.
Calcium depletion in rabbit myocardium. Calcium paradox protection by hypothermia and cation substitution.
Authors: Rich T L , Langer G A
Published: June 2012

The purpose of this study was to define further the basis of control of myocardial membrane permeability by further examination of the "calcium paradox." To this end, the protective effect of hypothermia and addition of micromolar amounts of divalent cations during the Ca-free perfusion period were studied. Damage during Ca++ repletion to the isolated arterially perfused, interventricular rabbit septum was assessed by contracture development, loss of developed tension, and loss of 42K and creatine kinase. Progressive hypothermia prolongs the time of Ca-free perfusion needed to cause similar 42K, creatine kinase and developed tension losses upon Ca++ repletion. Complete protection against the Ca-paradox after 30-60 minutes Ca-free perfusion is seen at 18 degree C. The inclusion of 50 microM Ca++ during 30 minutes "Ca-free" perfusion also provides complete protection during Ca++ repletion i.e., there was full mechanical recovery with no 42K or creatine kinase loss. Other divalent cations perfused in 50 microM concentrations during the Ca-free period exhibited variable ability to protect when Ca++ was reperfused. The order of effectiveness (Ca++ greater than Cd++ greater than Mn++ greater than Co++ greater than Mg++) was related to the crystal ionic radius, with those cations whose radii are closest to that of Ca++ (0.99 A) exerting the greatest protective effect. The cation sequence for effectiveness in Ca-paradox protection is the same sequence for potency of excitation-contraction uncoupling. The mechanism of hypothermic protection is likely a phase transition in the membrane lipids (from a more liquid to a less liquid state) which stabilizes membrane structure and preserves Ca++ permeability characteristics during the Ca-free period. The mechanism of protection via cation addition is perhaps a cation's ability to substitute for Ca++ (dependent on unhydrated crystal ionic radius) at critical sarcolemmal binding sites to preserve control of Ca++ permability during the Ca-free period.
Ventricular activation patterns of spontaneous and induced ventricular rhythms in canine one-day-old myocardial infarction. Evidence for focal and reentrant mechanisms.
Authors: El-Sherif N , Mehra R , Gough W B , Zeiler R H
Published: June 2012

We studied isochronal maps of ventricular activation during spontaneous multiform ventricular rhythms (rates 120-190/min) and pacing-induced ventricular tachyarrhythmias (rate 230-450/min) in dogs 1 day after myocardial infarction. Recordings were obtained from the entire epicardial surface and from selected endocardial and intramural sites utilizing a computerized multiplexing technique. Spontaneous ventricular rhythms had a focal origin from the surviving subendocardial Purkinje network underlying the infarction and showed frequent shift of the pacemaker site. On the other hand, fast ventricular tachyarrhythmias were consistently induced in the same dogs by bursts of rapid ventricular pacing or programmed premature stimulation and had a tendency to degenerate into ventricular fibrillation. Pacing-induced rhythms were due to reentrant activation that developed mainly in the surviving, electrophysiologically abnormal, epicardial layer overlying the infarction. The last stimulated heat that initiated reentry resulted in a continuous arc of functional conduction block and two slowly circulating activation fronts around both ends of the arc of block. The activation fronts rejoined on the distal side of the arc of block before breaking through the arc to reactivate an area proximal to the block. This resulted in splitting of the initial single arc of block into two separate arcs. Reentrant activation subsequently continued as two synchronous circuits which conducted in clockwise and counterclockwise directions, respectively. Reentry spontaneously terminated when the leading edge of both reentrant circuits encountered refractory tissue and failed to advance. The presence of two synchronous circuits was the hallmark of a stable reentrant activation. The development of three or more asynchronous circuits resulted in an activation pattern that was "prefibrillatory." This pattern was seen to develop during pleomorphic ventricular rhythms and ventricular tachycardias of the torsades de pointes type that degenerated into ventricular fibrillation. Ventricular fibrillation was maintained by continuously changing multiple asynchronous circuits. The transition from a stable reentrant activation pattern to that of ventricular fibrillation was probably related to nonhomogeneous shortening of refractoriness in different parts of the myocardium.
Attenuation of nephrotoxic acute renal failure in the dog with angiotensin-converting enzyme inhibitor (SQ-20,881).
Authors: Lindner A , Cutler R E , Bell A J
Published: June 2012

Angiotensin-converting enzyme inhibitor was used in dogs with uranyl nitrate-induced acute renal failure to evaluate (1) a possible protective effect of angiotensin blockade and (2)the role of angiotensin II in the generation of renal failure in this model. Angiotensin-converting enzyme inhibitor treatment attenuated the fall in glomerular filtration rate and renal blood flow during the first 6 hours after injection of the nephrotoxic agent. A protective effect of similar magnitude was observed whether angiotensin-converting enzyme inhibitor treatment preceded, or shortly followed, the administration of uranyl nitrate. This indicates that angiotensin-converting enzyme inhibitor delivery to its intrarenal site of action remains effective after administration of the nephrotoxin. In addition, protection of glomerular filtration rate correlated with sodium and renal solute excretion. However, combined treatment with angiotensin-converting enzyme inhibitor and furosemide enhanced solute excretion but did not further improve the protection of renal function. Finally, the protective effects of angiotensin-converting enzyme inhibitor on renal function and hemodynamics were abolished by intravenous indomethacin. In conclusion, early, continuous blockade of angiotensin II protects partially against th initiation of acute renal failure. These findings support a major pathogenic role for angiotensin II in the generation phase of acute renal failure in this model. Furthermore, they suggest that an imbalance between vasoconstrictive (angiotensin II) and vasodilating factors (prostaglandins) may be operative in the early phase of uranyl nitrate-induced acute renal failure in the dog.
Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent.
Authors: Solaro R J , Rüegg J C
Published: June 2012

AR-L 115BS, a benzimidazole derivative, is a positive inotropic agent that has been shown to increase active tension development and unloaded shortening velocity of chemically skinned heart muscle preparations at submaximal activating levels of free Ca++. We measured the effect of AR-L on relations between free Ca++, bound Ca++ and ATPase activity of dog cardiac myofibrils. At pCa 6, 100-300 micrometers AR-L increased myofibrillar ATPase activity maximally by about 30%. The concentration of AR-L giving half-maximal activation of myofibrillar ATPase activity was about 10 micrometers, and is similar to plasma concentrations associated with elevated contractility in intact animals. There was no effect of AR-L on myofibrillar ATPase activity at pCa 5 or 8, and the relation between pCa and percent activation of myofibrillar ATPase activity was shifted to the left by 0.4-0.5 pCa units in the presence of 100 micrometers AR-L. Calcium binding by cardiac myofibrils was increased by AR-L in the presence and absence of MgATP by 0.2-0.3 nmol/mg myofibrillar protein over a broad range of free Ca++ concentrations, a result suggesting that AR-L increases the affinity of myofibrillar troponin C for Ca++. The shift in the pCa giving half maximal and myofibrillar ATPase activity induced by raising the free Mg++ from 1.0 to 10 mm was unaffected by AR-L. These results indicate that the positive actions of AR-L 115BS on cardiac contractility may involve direct activation of myofibrils by virtue of an increased affinity of thin filament receptors for Ca++.
Cardiovascular reflex modulation of plasma catecholamine concentrations in the anesthetized cat.
Authors: Heesch C M , Bishop V S
Published: June 2012

The purpose of this study was to examine the role of carotid sinus and cardiopulmonary mechanoreceptors in the reflex control of adrenal medullary catecholamine secretion. Afferent input from carotid sinus and cardiopulmonary mechanoreceptors was decreased by carotid occlusion or cervical vagal cold block, respectively. Increases in arterial pressure were significantly greater when either intervention was tested in the presence of the other, with the role of the carotid sinus baroreflex being dominant. Neither carotid occlusion nor vagal cold block resulted in a significant increase in plasma epinephrine or norepinephrine concentrations. However, carotid occlusion during vagal block caused a significant increase in plasma epinephrine (+87%) and norepinephrine concentrations (+128%). Likewise, vagal block during carotid occlusion increased plasma epinephrine (+82%) and norepinephrine concentrations (+73%). Similar experiments performed in a group of chemically sympathectomized animals (pre-treated with 50 mg/kg 6-hydroxydopamine) indicted that adrenal medullary norepinephrine as well as epinephrine release could be modulated by the carotid sinus and cardiopulmonary reflexes. Mean arterial blood pressure and heart rate were significantly lower in 6-hydroxydopamine-treated animals, compared with untreated controls. Although of lesser magnitude, responses to carotid occlusion and vagal block in 6-hydroxydopamine-treated animals were qualitatively similar to those in untreated animals. Plasma catecholamine concentrations did not increase from either manipulation. However, when the second manipulation was added to the first, significant increases occurred. We conclude from these data that both the carotid sinus and cardiopulmonary reflexes modulate the release of adrenal catecholamines. An interaction between the two reflexes exists whereby the influence of one reflex on catecholamine secretion is apparent only in the absence of the other input.
Direct effects of cholinergic stimulation on ventricular automaticity in guinea pig myocardium.
Authors: Rardon D P , Bailey J C
Published: June 2012

The purpose of these experiments was to determine whether muscarinic cholinergic agonists exerted a negative chronotropic effect in the absence of endogenous norepinephrine in isolated guinea pig ventricular myocardial strips. The chronotropic response to physostigmine (10(-6) M) in control, reserpine-pretreated animals, and in the presence of increased norepinephrine release induced by superfusion of tyramine (10(-5) M), was studied. The control rates in the control, reserpine-pretreated, and tyramine-treated groups were 106 +/- 40, 93 +/- 31, 109 +/- 28/min, respectively. Propranolol (10(-6) M) produced a 23% slowing in rate in control animals and an 8% slowing in reserpine pretreated animals (P less than 0.01), suggesting basal secretion of norepinephrine. Tyramine (10(-5) M) produced a 28% increase in rate in control animals (P less than 0.05) and tyramine (10(-4) M) produced no increase in reserpine-pretreated animals. Physostigmine produced similar negative chronotropic response in control, reserpine-pretreated, and tyramine-treated groups of 45, 49, and 28%, respectively. Physostigmine produced no change in measured Purkinje fiber action potential characteristics, except for a decreased rate of spontaneous diastolic depolarization. Our results demonstrate that physostigmine slows the spontaneous rate in control, reserpine-pretreated and tyramine-treated groups, indicating that muscarinic cholinergic agonists exert a direct negative chronotropic effect at postjunctional cell surface receptors, independent of the presence or level of adrenergic tone.
Cardiovascular reflexes arising from the gallbladder of the cat. Effects of capsaicin, bradykinin, and distension.
Authors: Ordway G A , Longhurst J C
Published: June 2012

We have studied the cardiovascular responses which can be evoked when the gallbladder is stimulated pharmacologically or mechanically. To determine the potential for reflex cardiovascular activation, we applied capsaicin, a selective thin-fiber agonist, to the serosal surface of the gallbladder. This algesic substance evoked cardiovascular responses which included increases in mean arterial pressure (MAP) by 14%, heart rate (HR) by 3%, left ventricular dP/dt at 40 mm Hg developed pressure (dP/dt DP40) by 14%, and systemic vascular resistance (SVR) by 19%. There were no demonstrable effects on the cardiovascular system when this same substance was applied to the surface of the liver. Bilateral vagotomy at the level of the diaphragm did not alter the responses to capsaicin. Right atrial overdrive pacing did not reduce the positive inotropic effect elicited when the gallbladder was stimulated. Removal of the celiac and superior mesenteric ganglia, or selective denervation of the gallbladder, abolished the cardiovascular responses which were evoked previously. beta-Adrenergic blockade, however, abolished only the reflex chronotropic and intropic responses. Thus, the potential for eliciting reflex cardiovascular alterations by stimulating gallbladder afferents with capsaicin was established. In subsequent studies, stimulating the gallbladder with bradykinin, an endogenous polypeptide, evoked a reflex activation of the cardiovascular system similar to that seen with capsaicin (MAP = 14%; HR = 4%; dP/dt DP40 = 18%; SVR = 14%). These reflex responses were dose dependent, were produced by mucosal as well as serosal application of this substance, and were eliminated by bilateral splanchnic nerve action. In contrast to capsaicin and bradykinin, distension of the gallbladder did not cause any cardiovascular alterations. We conclude that stimulation of gallbladder afferents by the algesic substance capsaicin or by bradykinin, an endogenous substance that under certain conditions may be formed in bile, can induce significant reflex activation of the cardiovascular system.
Mechanism of Ca++ antagonist-induced vasodilation. Intracellular actions.
Authors: Saida K , van Breemen C
Published: June 2012

We studied the effects of Ca++ antagonists on intact and skinned muscles of rabbit mesenteric artery. Intact muscle contractions were inhibited by 10(-6) M diltiazem, whereas greater levels were required to abolish contractions in skinned muscle fibers. In contrast, nisoldipine had no effect on skinned muscle contractions, although it inhibited, almost completely, the contraction of intact muscle at concentrations below 10(-6) M. In the presence of EGTA, norepinephrine-induced contractions result from a release of Ca++ from an intracellular store. Diltiazem inhibited these contractions at concentrations between 10(-6) and 10(-4) M. Higher doses were required in studies with skinned muscle preparations. Unlike diltiazem, nisoldipine only partially inhibited the Ca++-free norepinephrine-induced contractions in the range of 10(-7) to 10(-5) M. From these results, we assumed that at low concentrations (below 10(-6) M), diltiazem induced relaxation by blocking Ca++ influx, whereas at relatively high concentrations (above 10(-6) M), an inhibition of Ca++ release from an intracellular store also occurred. A similar conclusion was reached regarding the mechanism whereby nisoldipine inhibits force developments.
Behavior of left ventricular mechanoreceptors with myelinated and nonmyelinated afferent vagal fibers in cats.
Authors: Gupta B N , Thames M D
Published: June 2012

The purpose of this study was to determine the behavior of left ventricular mechanoreceptors with myelinated vagal afferents and to compare them with endings with nonmyelinated vagal afferents. Single unit activity was recorded from 13 endings with nonmyelinated vagal afferents (conduction velocity 2.1 +/- 0.3 m/sec) and from 16 endings with myelinated vagal afferents (conduction velocity 7.3 +/- 1.3 m/sec). Resting discharge frequencies of nonmyelinated afferents and of myelinated vagal afferents were 1.7 +/- 0.3 and 2.7 +/- 0.5 imp/sec (P less than 0.1), respectively (at left ventricular end diastolic pressure of 6 mm Hg for both groups). Ten of 16 myelinated vagal afferents had pulse synchronous discharge under basal condition, whereas only 3 of 13 nonmyelinated vagal afferents had such activity. During aortic occlusion, the discharge of myelinated vagal afferents increased 1.7 +/- 0.3 imp/sec per mm Hg, whereas nonmyelinated vagal afferents increased significantly (P less than 0.05) less (0.5 +/- 0.1 imp/sec per mm Hg). Discharge for both groups was linearly related to left ventricular end-diastolic pressure but not to left ventricular systolic pressure. Increases in left ventricular systolic pressure alone did not increase firing for either group. During aortic occlusion, the maximum discharge rates of myelinated vagal afferents (43 +/- 7 imp/sec) were significantly higher than those of nonmyelinated vagal afferents (14 +/- 3 imp/sec) at left ventricular end-diastolic pressure of 30 +/- 2 and 24 +/- 2 mm Hg, respectively. Both groups increased their discharge during volume expansion with myelinated vagal afferents showing greater sensitivity than nonmyelinated vagal afferents. All endings studied were in the inferoposterior wall of the left ventricle. All nonmyelinated vagal afferents were in or near the epicardium. In contrast, myelinated vagal afferents were equally distributed between the endocardium and the epicardium. Myelinated vagal afferents had discrete receptive fields (1-2 mm2) whereas those of nonmyelinated vagal afferents were much larger (1 cm2). In conclusion, the discharge of left ventricular endings with nonmyelinated vagal afferents and myelinated vagal afferents both appear to be determined mainly by changes in left ventricular end-diastolic pressure. They may be located at different depths in the left ventricular wall. Myelinated vagal afferents have greater sensitivity and maximum firing frequencies than nonmyelinated vagal afferents.
Is there a serotonin-induced hypertensive coronary chemoreflex in the nonhuman primate?
Authors: Cornish K G , Zucker I H
Published: June 2012

The purpose of this study was to investigate the nature of the serotonin-induced coronary chemoreflex in the conscious monkey. Ten chronically prepared and four acute monkeys were used in this study. Five chronically prepared animals had catheters in the left atrium, ascending aorta, descending aorta, and, bilaterally, in the common carotid arteries. In addition, Silastic catheters were placed next to both vagi to permit vagal block with 2% lidocaine. Serotonin was injected (12-200 micrograms/kg) into the left atrium, ascending aorta, descending aorta, or, bilaterally, into the carotid arteries while blood pressure, heart rate, and respiratory movements were recorded. Injections of serotonin were associated with hypertension and bradycardia followed by tachycardia, all of which were preceded by a cough response. Atropine blocked the bradycardia, whereas atropine and phentolamine eliminated the cardiovascular components of the reflex. Vagal blockade eliminated the bradycardia but otherwise did not alter the response to left atrial serotonin. Three monkeys were prepared with aortic and left atrial catheters. Subsequently, they were subjected to sinoaortic deafferentation. Serotonin injected into these animals did not alter blood pressure or respiration. The results of this study show that serotonin injected into the left atrium of the conscious monkey produces respiratory and cardiovascular alterations by its effect on aortic and carotid chemoreceptors, and that there is no coronary chemoreflex in the conscious monkey.
Active transport and inotropic state in guinea pig left atrium.
Authors: Lechat P , Malloy C R , Smith T W
Published: June 2012

Although the positive inotropic effect of cardiac glycosides correlates well with inhibition of Na+ pump activity in many preparations, digitalis at low concentrations (10(-9) to 10(-8) M) may produce an apparent stimulation of monovalent cation transport in isolated intact myocardium or produce an inotropic effect that does not correlate with pump inhibition. Digitalis is known to modify tissue metabolism of endogenous neurotransmitters that may affect inotropic state, Na,K-ATPase activity, and K+ permeability. We examined the interactions of low concentrations of ouabain with adrenergic and cholinergic influences in isolated guinea pig left atria stimulated at 3.3 Hz in which inotropic state and monovalent cation transport (measured as 86Rb+ uptake) were assessed simultaneously. Ouabain (10(-9) M) stimulated Rb+ transport (+25%) without an inotropic response; the stimulatory effect on transport was abolished by propranolol or atropine pretreatment. In atria pretreated with atropine, 10(-8) M ouabain produced a small positive inotropic effect (+10%) without measurable associated Na+-K+ pump inhibition. This inotropic response was abolished in catecholamine-depleted atria. Ouabain (10(-7) M) always produced a positive inotropic response (about +25%) independent of catecholamine depletion, beta-adrenergic blockade, or muscarinic blockade, but Rb+ uptake inhibition was observed only in beta-adrenergically-blocked atria. In all preparations, ouabain concentrations greater than 10(-7) M caused an inotropic response associated with pump inhibition. At concentrations 3 X 10(-7) M and higher, mechanical toxicity was observed in all preparations except those pretreated with propranolol. Incubation with low concentrations of ouabain did not modify the inotropic response to isoproterenol. At concentrations of isoproterenol sufficient to stimulate Rb+ transport by 25%, there was a large (+80%) inotropic response. We conclude first, that, in guinea pig atria exposed to ouabain, the mechanism as well as the extent of inotropic response and of monovalent cation transport modification is concentration dependent, second, that at low concentrations (1-10 X 10(-9) M), in vitro inotropic and monovalent cation transport responses are in part mediated by an effect of ouabain on endogenous neurotransmitters; and third, that in this preparation at concentrations between 10(-9) and 10(-7) M ouabain, monovalent cation transport as measured by tissue 86Rb+ uptake does not correlate with inotropic response.
Dynamic vagal control of pacemaker activity in the mammalian sinoatrial node.
Authors: Jalife J , Slenter V A , Salata J J , Michaels D C
Published: June 2012

Dynamic heart rate control by parasympathetic nervous input involves feedback mechanisms and reflex bursting of efferent cardiac vagal fibers. Periodic vagal bursting induces phasic changes in sinoatrial cycle length and can entrain the pacemaker to beat at periods that may be identical to those of the vagal burst. We investigated the electrophysiological basis of these phenomena in isolated sinus node preparations (rabbit, cat, and sheep). In the presence of propranolol (3.9 X 10(-6)M), relatively brief (50-150 msec) trains of stimuli, applied onto the endocardial surface of the preparation, activated postganglionic vagal terminals and induced a brief hyperpolarization of sinoatrial pacemaker cells. This vagally mediated hyperpolarization could alter the pacemaker rhythm by an amount that depended on its duration and its position in the cycle, as well as on the duration of the free-running pacemaker period. When the free-running period was sufficiently long and the hyperpolarization was induced sufficiently early in the spontaneous cycle, a "paradoxical" acceleration of the pacemaker rhythm ensued. Phasic changes were plotted on phase-response curves, constructed by scanning systematically the sinoatrial pacemaker period with single or repetitive vagal trains. These phase-response curves enabled us to predict the entrainment characteristics and the levels of synchronization of the pacemaker to the vagal periodicity. The overall data explain the cellular mechanisms involved in the phasic effects of brief vagal discharges on sinoatrial periodicity, and provide conclusive evidence for the prediction that repetitive vagal input is capable of forcing the cardiac pacemaker to beat at rates that can be faster or slower than the intrinsic pacemaker rate. These data should improve our knowledge of the dynamic control of heart rate by neural reflexes and aid in our understanding of rhythm disturbances generated by the interaction of the cardiac pacemaker with vagal activity.
The effects of isoproterenol and ouabain on oxygen consumption, lactate production, and the activation of phosphorylase in coronary artery smooth muscle.
Authors: Paul R J
Published: June 2012

In previous work, oxidative metabolism in vascular smooth muscle was found to be correlated with isometric force; aerobic lactate production, however, was found to be substantial and correlated with Na-K transport processes (Paul et al., 1979; Paul, 1980). In this work, the role of glycogen phosphorylase in this unusual functional compartmentalization of of vascular energy metabolism was investigated. Isometric force, oxygen consumption, lactate production, and the level of phosphorylase activity were measured in porcine coronary arterial segments. For comparison with previous studies, phosphorylase activity was also measured in rabbit aorta. Added potassium chloride induced a contracture in which oxygen consumption, lactate production, and phosphorylase activity all increased. Ouabain also induced a contracture, and an increase in oxygen consumption and phosphorylase activity. However, lactate production was inhibited. Isoproterenol, when added to a potassium chloride-induced contracture, elicited a relaxation in isometric force, and oxygen consumption returned to basal levels; however, lactate production and phosphorylase activity remained at the previously elevated levels. Isoproterenol alone had only marginal effects on all parameters studied. The results indicate that the role of phosphorylase in vascular metabolism is complex and unlikely to be a rate-limiting factor for the observed aerobic glycolysis. The high levels of phosphorylase activity observed in the absence of actomyosin interaction support a mechanism of beta-adrenergic relaxation in which the sensitivity of actin-myosin interaction to calcium ion is decreased.
Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis.
Authors: Gallagher K P , Matsuzaki M , Osakada G , Kemper W S , Ross J
Published: June 2012

Relationships between regional myocardial perfusion and transmural function, both during treadmill exercise and at rest, were examined in conscious dogs with varying degrees of coronary stenosis produced by a hydraulic occluder. In 13 dogs we measured myocardial blood flow with microspheres (10-12 microns in diameter) and regional systolic wall thickening (%). During exercise with coronary stenosis, myocardial blood flow was characterized by nonuniform distribution, and associated with regional dysfunction. The relationships between normalized myocardial blood flow and normalized %wall thickening during exercise with coronary stenosis were linear, with significantly different slopes (mean myocardial blood flow: y = 1.23x - 0.16, r = 0.93; subendocardial myocardial blood flow: y = 1.50x - 0.02, r = 0.86; subepicardial myocardial blood flow: y = 0.83x - 0.18, r = 0.87). To fill the gap between available subendocardial and subepicardial data during exercise with coronary stenosis and control points, however, would require nonlinear components. In 10 of the dogs, coronary stenosis at rest was also produced to compare regional myocardial blood flow - %wall thickening relations at rest with those during steady state exercise. The absolute mean myocardial blood flow - %wall thickening relation during exercise with coronary stenosis (y = 11.6x - 1.9, r = 0.90) was significantly shifted rightward from the resting relation (y = 25.3x -2.1, r = 0.80). However, when changes in %wall thickening were plotted vs. myocardial blood flow per beat, the relationships at rest and exercise were nearly superimposable. Likewise, relations between normalized myocardial blood flow and changes in %wall thickening at rest and exercise were not significantly different. We conclude: %wall thickening during exercise is directly related to changes in mean myocardial blood flow but is related in nonlinear fashion to changes in subepicardial and subendocardial myocardial blood flow; %wall thickening may provide a reliable index of the relative transmural flow distribution during exercise as well as at rest; during brief bouts (5-8 minutes) of exercise with coronary stenosis, the relationship between stabilized regional contractile dysfunction and level of myocardial blood flow per beat is the same as that during coronary stenosis at rest.
Evidence that serotonin receptors mediate the cutaneous vasoconstriction produced by 5-hydroxytryptamine in canine forelimbs.
Authors: Dobbins D E , Adamski S W , Lokhandwala M F , Grega G J
Published: June 2012

The effects of local intra-arterial infusions of serotonin (5 or 25 micrograms base/min) or norepinephrine (1 or 5 micrograms base/min) on cutaneous (skin) and skeletal muscle vasculatures were investigated in canine forelimbs perfused at constant flow in dogs anesthetized with pentobarbital. Norepinephrine produced dose-related constriction of the skin and skeletal muscle vasculatures. In the cutaneous vascular circuit, norepinephrine produced large artery, small vessel, and large vein constriction. The increase in cutaneous vascular resistance was primarily due to an increase in small vessel resistance. Serotonin did not increase skeletal muscle vascular resistance but produced marked cutaneous vasoconstriction subsequent to large artery and large vein constriction. The small vessels, if anything, tended to dilate. The skin and skeletal muscle vascular responses to serotonin and norepinephrine were similar in innervated and acutely denervated forelimbs. Phentolamine pretreatment completely blocked all vascular actions of norepinephrine, and largely inhibited the cutaneous vasoconstriction produced by the infusion of the low dose of serotonin. However, the cutaneous large artery and large vein constriction produced by the infusion of the high dose of serotonin was not affected by phentolamine pretreatment. Cyproheptadine pretreatment blocked or largely inhibited the cutaneous vasoconstriction produced by serotonin only in doses which also inhibited norepinephrine and vasopressin cutaneous vasoconstriction. Pretreatment with methysergide blocked or largely inhibited the cutaneous large artery and large vein constriction produced by infusions of serotonin. Norepinephrine and vasopressin produced significant vasoconstriction in the presence of methysergide. These data suggest that the cutaneous large artery and large vein constriction produced by serotonin is not due to the activation of postjunctional alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Resting and exercise renal blood flows in immature ovine aortic coarctation. Impact of gradient relief.
Authors: Lock J E , Kulik T J , Green T P , Niemi T , Einzig S
Published: June 2012

The primary purpose of this study was to determine whether a neonatally induced thoracic aortic coarctation reduces renal blood flow during physiological stress (treadmill exercise), and whether relief of the gradient returned renal blood flow during exercise to normal. Two ancillary questions were also addressed: dose a coarctation after the responses of enteric and other visceral vascular beds to treadmill exercise? Eight newborn lambs that underwent sham thoracotomy with placement of left atrial lines served as controls; in seven lambs we also created a recently described form of dilatable juxtaductal coarctation. This preparation is unique in that, like human coarctation, the obstruction does not get worse as the animal grows. Rest and exercise vascular pressures and regional blood flows were determined 2-2 1/2 months after surgery. Coarctations were relieved with balloon dilation angioplasty catheters, inserted percutaneously. Postdilation rest and exercise hemodynamic studies were performed, at the same level of exercise, 24 hours after dilation. Renal blood flow did not change with exercise in the control animals. In lambs with coarctation, renal blood flow fell (-22%, P less than 0.01) during exercise. Unexpectedly, an exercise-induced fall in renal blood flow (-22%, P less than 0.001) persisted even after effective relief of the coarctation (descending aortic blood pressure fell 25% with exercise predilation, but remained unchanged with exercise postdilation). Blood flow to the terminal ileum and cecum followed a qualitatively similar pattern to that of renal blood flow in control, predilation, and postdilation lambs, and this pattern was distinct from that of other enteric and visceral organ flows. These results demonstrate an expected abnormality in the regulation of exercise renal blood flow in lambs with coarctation of the aorta; however, the persistence of this abnormality after effective gradient relief does not support the previously advanced theory that postcoarctation hypertension is largely nonrenal in origin. The apparent similarity between ileocecal and renal blood flow control under these circumstances may provide a clue to the known predilection of the terminal ileum to suffer ischemic injury.