Right ventricular oxygen supply/demand balance in exercising dogs.

This is the first investigation of right ventricular (RV) myocardial oxygen supply/demand balance in a conscious animal. A novel technique developed in our laboratory was used to collect right coronary (RC) venous blood samples from seven instrumented, conscious dogs at rest and during graded treadmill exercise. Contributions of the RV oxygen extraction reserve and the RC flow reserve to exercise-induced increases in RV oxygen demand were measured. Strenuous exercise caused a 269% increase in RV oxygen consumption. Expanded arteriovenous oxygen content difference (A-V(Delta)O2) provided 58% of this increase in oxygen demand, and increased RC blood flow (RCBF) provided 42%. At less strenuous exercise, expanded A-V(Delta)O2 provided 60-80% of the required oxygen, and increases in RCBF were small and driven by increased aortic pressure. RC resistance fell only at strenuous exercise after the extraction reserve had been mobilized. Thus RC resistance was unaffected by large decreases in RC venous PO2 until an apparent threshold at 20 mmHg was reached. Comparisons of RV findings with published left ventricular data from exercising dogs demonstrated that increased O2 demand of the left ventricle is met primarily by increasing coronary flow, whereas increased O2 extraction makes a greater contribution to RV O2 supply.

Exercise training reduces ischemic myocardial dysfunction.

PURPOSE: This study tested the hypothesis that exercise training improves myocardial blood flow and regional myocardial contractile function in a lateral border zone located adjacent to the ischemic zone during coronary artery occlusion. METHODS: Fourteen dogs were subjected to either 12 wk of dynamic exercise training or cage rest. Dogs were anesthetized and instrumented to assess regional myocardial contractile function (percent segment length shortening and rate of shortening) and regional myocardial blood flow (tracer microspheres) in the central ischemic, lateral border, and nonischemic zones. Measurements were made preocclusion and at 2 min and 3 h after occlusion of the left anterior descending coronary artery (CAO). RESULTS: Contractile function and regional myocardial blood flow were not affected by CAO in the nonischemic zone in both cage-rested and exercise trained dogs. Regional myocardial contractile function and blood flow in the lateral border zone were significantly higher in exercise trained dogs compared with cage-rested dogs, both at 2 min and 3 h after CAO. Ischemic dysfunction was similar in the central ischemic zone in both cage-rested and exercise trained dogs both at 2 min and 3 h after CAO. Regional myocardial blood flow was similarly reduced in the ischemic zone in both groups after 2 min of CAO, but was significantly higher in the inner (subendocardial) region of the exercised trained hearts after 3 h (P < 0.05). CONCLUSION: These data suggest that there was greater border zone perfusion in exercise trained animals during prolonged CAO, which was associated with significantly improved myocardial contractile function.

Exercise training increases creatine kinase capacity in canine myocardium.

INTRODUCTION: The creatine kinase (CK) energy shuttle of cardiomyocytes channels metabolic energy from the mitochondria to sites of energy utilization at contracting myofibrils and sarcolemmal and sarcoplasmic reticular ion pumps. Although plasticity of the myocardial CK system in response to hemodynamic overload has been repeatedly demonstrated, the effects of aerobic exercise training on myocardial CK are less well understood. This investigation tested the hypothesis that aerobic exercise training increases the capacity of the CK system in canine myocardium. METHODS: Mongrel dogs were conditioned by a 9-wk treadmill running program or cage-rested for 4 wk. Total CK activity was measured colorimetrically; CK(MB) was separated from other CK isoforms and measured by electrophoresis. RESULTS: Relative to sedentary controls, training increased left ventricular total CK activity 46% (P < 0.05) but did not alter total CK activity in right ventricular myocardium. Also in left ventricular myocardium, training increased CK(MB) isoenzyme activity 4.5-fold and the CK(MB) fraction of total CK threefold from 1.1+/-0.4 to 3.4+/-0.8% (P < 0.05). In contrast to left ventricle, CK(MB) activity and its fraction of total CK activity were not altered by training in right ventricular myocardium. CONCLUSIONS: Aerobic exercise training increases total myocardial CK activity and CK(MB) content in canine left ventricular myocardium, although CK(MB) remains a minor component of the myocardial CK system. The right ventricular CK system was not affected by training.

Cardiovascular disease and obstructive sleep apnea: implications for physicians.

Obstructive sleep apnea (OSA) has been strongly associated with several cardiovascular disorders during the past decade, and studies suggested that there might be a causal relationship. Recent studies have described several pathophysiologic mechanisms that are active in OSA and may participate in the development of cardiovascular disorders. Primarily, the repetitive respiratory events that occur in OSA cause hypoxia, hypercapnea, arousals, or disrupted sleep singly or in combination. These abnormal physiologic events result in increased sympathetic outflow, alterations in blood pressure control mechanisms, dysfunctional ventilatory regulation, and vascular alterations. As a consequence of the relative impact and the genetic predisposition, these pathophysiologic alterations may lead to or complicate a wide variety of cardiovascular disorders. Frequently, patients who have OSA present with complaints of excessive daytime sleepiness, chronic fatigue, snoring, morning headache, and nocturnal arousals. Difficult-to-control hypertension, recurrent exacerbations of congestive heart failure, and nocturnal angina are common cardiovascular manifestations of undiagnosed OSA. This article reviews the major cardiovascular disorders associated with OSA and the pathophysiologic mechanisms associated with their development.

Exercise training enhances glycolytic and oxidative enzymes in canine ventricular myocardium.

Aerobic exercise training evokes adaptations in the myocardial contractile machinery that enhance cardiac functional capacity; in comparison, the effects of training on the myocardium's energy generating pathways are less well characterized. This study tested the hypothesis that aerobic exercise training can increase the capacities of the major pathways of intermediary metabolism in canine myocardium. Mongrel dogs were conditioned by a 9-week treadmill running program or cage rested for 4 weeks. Exercise conditioning was evidenced by 26% and 22% decreases (P<0.05) in respective heart rates at rest and during submaximal exercise and by a 40% increase (P<0.05) in citrate synthase (CS) activity of the vastus lateralis. Glycolytic, TCA cycle, and beta-oxidative enzymes were assayed in myocardial extracts at 37 degrees C. Relative to sedentary controls, training increased glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity by 49% in left and 33% in right ventricle, and pyruvate kinase, CS, and 3-hydroxyacyl CoA dehydrogenase (HADH) activities by 74%, 91%, and 77%, respectively, in left ventricle (P<0.05). Immunoblotting further confirmed that training increased left ventricular contents of CS and GAPDH. Other measured enzymes (hexokinase, phosphofructokinase, lactate dehydrogenase, alpha-ketoglutarate dehydrogenase, malate dehydrogenase) were not altered by training in either ventricle. Kinetic analyses revealed increased maximum rates but unaltered substrate affinities of GAPDH, CS and HADH following training. Thus, aerobic exercise training augments the intermediary metabolic capacity of canine myocardium by selectively increasing the concentrations of regulatory enzymes of glycolysis and oxidative metabolism.

Right coronary autoregulation in conscious, chronically instrumented dogs.

Right coronary (RC) autoregulation and right ventricular (RV) function were assessed in conscious dogs, chronically instrumented to measure RC flow and RC pressure (RCP) as a hydraulic occluder on the RC was inflated. Dogs were then anesthetized, and RC autoregulation and RV function were again assessed. In the conscious state, moderate RC autoregulation was present with closed loop gains (Gc) of 0.59-0.27 as RCP was reduced from 100 to 40 mmHg. In the anesthetized state, Gc was not significantly less than in the conscious state at RCP >50 mmHg. The range and potency of RV autoregulation were greater in both groups than for previously reported findings in anesthetized dogs with RC perfused by an extracorporeal system. RV contractile function was well maintained in conscious and anesthetized dogs at RCP >45 mmHg. We conclude the following: 1) modest RC autoregulation is present in the conscious dog, 2) anesthesia limits the range but not the degree of RC autoregulation, 3) extracorporeal perfusion systems appear to depress RC autoregulation, and 4) RV contractile function remains constant in both conscious and anesthetized dogs until RCP falls below 50 mmHg.

Exercise effect on canine and miniswine cardiac catecholamines and enkephalins.

Chronic exercise changes cardiac function and responsiveness to autonomic control. Catecholamines and enkephalins are neuroendocrine transmitters involved in autonomic regulation and signaling. We hypothesized that intermittent increased sympathetic stimulation caused by exercise training would decrease cardiac catecholamine and enkephalin content. Dogs and miniswine were exercise trained and hearts extracted for catecholamine and enkephalin measurements. Atrial catecholamine content is greater than ventricular content in dog heart which is in keeping with the greater atrial neuronal density. In contrast, porcine epinephrine content was evenly distributed across heart sections and norepinephrine content was greater on the right side than the left. Changes in miniswine and dog heart catecholamine content after exercise training were different. Canine cardiac norepinephrine content decreased and porcine norepinephrine content increased. This indicates a difference in cardiac adrenergic control in miniswine versus canines. Methionine-enkephalin (met-enk) distribution across canine heart is uniform, unlike the miniswine, where the atria contain more than the ventricles. Proenkephalin processing produces four met-enk sequences and one met-enk-arg-phe; despite this, ventricles of both species contain more met-enk-arg-phe immunoreactivity than met-enk. Therefore, proenkephalin processing is incomplete in heart tissue. Exercise training in the dog resulted in decreased cardiac met-enk, decreased left atrial met-enk-arg-phe, and increased ventricular met-enk-arg-phe. Porcine cardiac enkephalin concentration was unchanged by training. The changes in the enkephalins may be explained by changes in proenkephalin processing and/or release. Met-enk-arg-phe is particularly good at modulating vagal stimulation of the canine heart. The changes in tissue content seen after exercise training may be a result of the exercise-induced change in autonomic tone to the heart. These data suggest species dependent changes in autonomic regulation.

Limitation of cardiac output by a coronary alpha 1-constrictor tone during exercise in dogs.

This study was performed to examine whether an alpha 1-constrictor tone, which limits coronary functional hyperemia during exercise, imposes a significant limitation on global cardiac performance as determined by cardiac output (CO). Seven dogs were chronically instrumented to measure left ventricular pressure (LVP), maximum rate of rise of LVP (dP/dtmax), heart rate (HR), mean aortic pressure (AoP), circumflex blood flow velocity (CFV), and CO at rest and during submaximal exercise. Either the selective alpha 1-adrenergic antagonist prazo (0.5 mg) or the vasodilator adenosine was administered into the circumflex artery during exercise at 6.4 kilometers per hour (kph)/16% treadmill incline. Exercise caused significant increase in mean AoP, HR, LVP, dP/dtmax, CFV, stroke volume (SV), and CO, whereas systemic vascular resistance (SVR) was significantly reduced. After intracoronary alpha 1-blockade with prazosin, CFV, dP/dtmax, SV, and CO increased further (17 +/- 2, 19 +/- 3, 16 +/- 2, and 17 +/- 2%, respectively) without changing mean AoP, HR, or SVR. Comparable increases were observed when CFV was increased by a similar degree using the direct vasodilator adenosine. These results indicate that increasing coronary flow by removing a coronary alpha 1-constrictor tone with prazosin or by direct vasodilation with adenosine during submaximal exercise leads to an increase in myocardial oxygen supply and, as a result, cardiac pump performance (SV and CO).

Coronary alpha 1-adrenergic constrictor tone varies with intensity of exercise.

This study tested the hypothesis that an alpha-adrenergic coronary constrictor tone increases with the intensity of exercise and imposes a limitation on transmural myocardial blood flow and contractile function during strenuous levels of exercise. Nine (9) dogs were chronically instrumented to measure left circumflex blood flow (CBF), global myocardial contractile function (dP/dtmax), and regional myocardial contractile function (maximal rate of segmental shortening, dL/dtmax). The dogs were subjected to a graded sub-maximal exercise test with increasing workloads encompassing 4.8 kph and 6.4 kph, 0, 4, 8, 12, and 16% incline. On separate days, either vehicle (sterile water) or the specific alpha 1-adrenergic receptor antagonist prazosin (1 microgram.kg-1.min-1) was infused into the circumflex artery during exercise. Removal of an alpha 1-receptor mediated coronary constrictor tone resulted in a 15 +/- 7%, 24 +/- 9%, and 35 +/- 10% greater increase in CBF compared with vehicle at the three most strenuous levels of exercise, respectively. Regional left ventricular blood flow was measured using labeled microspheres in four (4) additional dogs. Endocardial and epicardial blood flow increased equally by 16% during exercise after prazosin, such that the endocardial/epicardial flow ratio did not change. The augmentation in CBF after alpha 1-blockade was associated with significant increases in both regional and global left ventricular contractile function. These studies indicate that a uniformly distributed transmural coronary alpha 1-constrictor tone increases in magnitude with increasing levels of exercise intensity and, as a result, imposes a significant limitation on myocardial function.

Coronary alpha 1-constrictor tone during renovascular hypertension.

BACKGROUND: A coronary alpha 1-adrenergic constrictor tone exists under conditions associated with increased sympathetic stimulation but not during resting conditions in the normal heart. During renovascular hypertension, elevated circulating angiotensin II may enhance sympathetic stimulation of the heart, even at rest. This study tested the hypothesis that an alpha 1-adrenergic constrictor tone imposes limitations on coronary blood flow in resting dogs after development of renovascular hypertension, exacerbates coronary alpha-constrictor tone during exercise, and increases coronary vascular adrenergic responsiveness. METHODS AND RESULTS: Left circumflex blood flow velocity (CFV), aortic pressure (AoP), and heart rate (HR) were examined in five quietly resting dogs during control conditions and after selective alpha 1-adrenergic blockade using an intracoronary injection of 0.5 mg prazosin. In the normotensive state, AoP was 87 +/- 7 mm Hg (mean +/- SD), HR was 105 +/- 25 beats per minute, and CFV was 28 +/- 6 cm/s. These parameters were not affected by alpha 1-adrenergic blockade. During submaximal exercise, removal of an alpha 1-adrenergic constrictor resulted in a 14 +/- 4% increase in CFV (P < .05). Two weeks after development of renovascular hypertension induced by stenosis of the left renal artery, mean AoP was 114 +/- 7 mm Hg (P < .05 versus normotensive state), HR was 111 +/- 28 beats per minute, and CFV was 21 +/- 8 cm/s. In contrast to the normotensive state, alpha 1-adrenergic blockade caused a 28 +/- 6% increase in CFV at rest (P < .05) and a 27 +/- 13% increase in CFV during exercise in the hypertensive state (P < .05 versus exercise before blockade and versus normotensive state). This resting coronary constrictor tone was associated with enhanced vasoconstrictor responsiveness to norepinephrine and phenylephrine. CONCLUSIONS: It appears that renovascular hypertension results in a significant coronary alpha 1-adrenergic constrictor tone in the resting dog and an enhanced constrictor tone during exercise.

Augmented coronary blood flow response to intracoronary norepinephrine after ventricular sympathectomy.

BACKGROUND: Ventricular sympathetic denervation may occur as a result of myocardial infarction or heart transplantation. The present study examined the time-dependent effects of surgical ventricular sympathectomy on coronary flow and myocardial contractile responses to intracoronary norepinephrine administration in conscious dogs. METHODS: Adult mongrel dogs (18-26 kg), were either ventricular sympathectomized or served as a sham-operated control. Animals were studied 2, 4, and 8 weeks after surgery. Measurements of left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure generation (dP/dtmax), maximum negative rate of segmental shortening (-dL/dtmax), heart rate, and mean circumflex flow velocity (CFV) were obtained before and after bolus administration of norepinephrine into the circumflex artery in doses ranging from 0.01 to 0.50 microgram. RESULTS: Intracoronary norepinephrine administration caused significant increases in LVSP, dP/dtmax, -dL/dtmax, heart rate, and CFV. After reaching a peak or maximum response, these variables returned to their respective preinjection values, except for CFV, which exhibited a biphasic response. CFV continued to decline below control levels, indicating a vasoconstrictor response to norepinephrine, before returning back to preinjection levels. With the 0.5-microgram dose of intracoronary norepinephrine, the percent increases in CFV were 124% +/- 25% and 105% +/- 15% (P < 0.05) at 2 and 4 weeks respectively, compared with the sham-operated controls, which only increased 56% +/- 15%. The response to the 0.5-microgram dose of norepinephrine at 8 weeks (61% +/- 6%) was not significantly different from control. Elevated myocardial contractile responses in the sympathectomized hearts were also evident at 2 and 4 weeks, but not at 8 weeks. The vasoconstrictor response to norepinephrine administration was not significantly different between sympathectomized and sham-operated hearts. Finally, there was no difference in the change in LVSP, dP/dtmax, or heart rate between any of the groups at any of the doses. CONCLUSIONS: These results suggest that a supersensitivity to the coronary functional hyperemic response after intracoronary norepinephrine is present in ventricular sympathectomized hearts, but a coronary constrictor supersensitivity does not exist.

Cardiac response to acute coronary artery occlusion in exercise-trained dogs.

Exercise training is thought to exert a beneficial effect on cardiovascular function, but its effect in the normal heart following acute coronary artery occlusion is still uncertain. Studies were performed in 12 untrained (UT) and 14 endurance-trained (ET) pentobarbital anesthetized dogs. Left ventricular pressure (LVP), heart rate (HR), percent regional myocardial segmental shortening (%SL), and peripheral coronary pressure (PCP) distal to the occlusion were measured during control conditions and during a 2-min circumflex artery occlusion (CAO). During CAO, LVP, dP/dtmax, and %SL in the ischemic region were significantly reduced in both UT and ET dogs. There was no significant difference between the two groups. In addition, PCP decreased to 27 +/- 5 mm Hg and 26 +/- 9 mm Hg in the UT and ET groups, respectively, during CAO indicating no difference in coronary collateral perfusion between the groups. Regional myocardial blood flow was measured using tracer microspheres in eight of the UT and six of the ET dogs, and the decrease in blood flow to the ischemic zone during CAO was similar in both groups. These results indicate that 12-wk of endurance training does not exert a protective effect on myocardial contractile function or on myocardial perfusion in the central ischemic region during CAO in the anesthetized dog.

Effects of a coronary alpha 1-constriction on transmural left ventricular flow and contractile function.

Modulation of myocardial contractile function and perfusion by alpha 1-adrenergic receptors were examined in anesthetized dogs during left stellate ganglion stimulation. In 11 dogs, stellate stimulation significantly increased heart rate, mean arterial pressure, left ventricular systolic pressure, maximal rate of left ventricular pressure generation, segmental shortening and rate of shortening in anterior and posterior ventricular regions, and myocardial oxygen extraction. Myocardial lactate extraction decreased. The selective alpha 1-adrenergic antagonist prazosin (0.5 mg) injected into the circumflex artery during stellate stimulation caused significant additional increases in maximal rate of left ventricular pressure generation by 19 +/- 5% and in rate of shortening in posterior subendocardium by 20 +/- 6%. No changes were observed in posterior subepicardial or anterior subendocardial segmental contractile function. Myocardial oxygen and lactate extractions returned to their control values following prazosin injection. Regional left ventricular perfusion was measured using tracer microspheres in five additional dogs. Stellate stimulation increased subepicardial and subendocardial perfusion by 30%. Prazosin increased both subepicardial and subendocardial perfusion by an additional 36%. Stellate stimulation increased norepinephrine concentration in the coronary sinus, but no further increase was noted after blockage of alpha 1-receptors by prazosin. Thus, during sympathetic stimulation, an alpha 1-vasoconstriction existed uniformly across the left ventricular wall. However, blockade of this vasoconstriction was associated with an increase in contractile function only in the deeper muscle layers.

An alpha-adrenergic coronary constriction during esophageal distention in the dog.

Previous work has shown an increase in sympathetic stimulation of the heart during chemical or mechanical irritation of visceral organs, but the involvement of the coronary circulation in such reflexes is not clear. In five preliminary experiments in anesthetized dogs, esophageal distention produced a sympathetic stimulation of the heart, as evidenced by an increase in heart rate, which was abolished by non-selective beta-adrenergic and muscarinic blockades. On the basis of these preliminary data, we further examined a sympathetic coronary constriction during acute esophageal distension in which any direct adrenergic coronary constriction was unmasked by muscarinic blockade with atropine (100 micrograms/kg, i.v.), and non-selective beta-adrenergic blockade with propranolol (1 mg/kg, i.v.). In seven dogs anesthetized with alpha-chloralose in an open-chest procedure, the esophagus was rapidly distended to a pressure of 36 +/- 2 mm Hg, which was not significantly different from the distending pressure used in the preliminary experiments. During esophageal distention, the mean circumflex blood flow decreased to 77 +/- 10% (SEM) of the predistention value. This decrease was statistically significant (p less than 0.05). There was no change in left ventricular pressure, mean arterial pressure dP/dtmax, or heart rate. Intracoronary administration of the nonselective alpha-adrenergic antagonist phentolamine completely abolished the reduction in mean circumflex coronary blood flow caused by esophageal distention in the presence of beta-adrenergic and muscarinic blockades. These results demonstrate a direct sympathetic coronary vasoconstriction elicited by esophageal distention. This vasoconstriction was due to activation of coronary alpha-adrenergic receptors.

Augmentation of coronary flow improves myocardial function in exercise.

We compared the effects of increasing coronary blood flow (CBF) by intracoronary alpha 1-adrenergic blockade or by a direct vasodilator in six chronically instrumented dogs undergoing submaximal exercise. On different days, CBF, left ventricular pressure (LVP), regional myocardial segment length (SL), and arterial blood pressure (ABP) were measured at rest, during strenuous exercise before administration of vasodilating agents, and during exercise after administration of the vasodilating agents prazosin (0.5 mg) or adenosine (10-100 micrograms/min continuous infusion) through an indwelling circumflex artery catheter. Exercise resulted in a significant increase in CBF, which was accompanied by significant increases in maximum rate of LVP generation (dP/dtmax), percentage of SL shortening (%SL) and maximum rate of SL shortening (dL/dtmax) in both the anterior and posterior regions of the left ventricle. As compared with the exercise level alone, prazosin administration or adenosine infusion during exercise significantly increased CBF by 22 and 26%, respectively. Furthermore, these increases in CBF were followed by significant increases in both dP/dtmax and dL/dtmax over exercise levels without prazosin administration or adenosine infusion. These results suggest that myocardial contractile function may be flow-limited under conditions of submaximal exercise and that coronary vasodilation, either by alpha 1-adrenergic blockade or by a direct vasodilator, improves contractile function.

Endurance training alters arterial baroreflex function in dogs.

The present study was designed to determine whether 12 wk of daily exercise alter autonomic neural control of the heart during baroreflex stimulation in healthy dogs. We studied 16 untrained and 12 endurance-trained anesthetized dogs which were instrumented to measure arterial blood pressure (AP), carotid sinus baroreceptor pressure (CBP), electrocardiogram (ECG), heart rate (HR), and R-R interval (RR). The arterial baroreflex was studied during hypertension caused by i.v. bolus infusion of phenylephrine, hypotension caused by i.v. bolus infusion of nitroprusside, and bilateral carotid occlusion (BCO) in which carotid sinus pressure was reduced to 41 +/- 2 mm Hg (mean +/- SEM). Arterial baroreflex sensitivity, which was assessed by determining the change in heart interval (i.e., change in RR) per unit change in systolic AP (delta RR/delta AP), was significantly lower during the hypertensive challenge in the trained dogs compared to the untrained dogs (2.2 +/- 0.3 vs 6.8 +/- 1.5 ms.mm Hg-1, respectively). Similarly, the delta RR/delta AP was substantially lower during the hypotensive challenge in trained dogs vs the untrained dogs (1.2 +/- 0.3 vs 1.8 +/- 0.4 ms.mm Hg-1, respectively). In addition, the HR response to the BCO was significantly less in trained dogs (22 +/- 2 bpm) vs untrained dogs (32 +/- 5 bpm). The open-loop gain (Go), which was used to quantitate the effectiveness of the carotid baroreflex to increase mean systemic AP during BCO, was similar in both untrained and trained dogs (2.9 +/- 0.6 and 2.4 +/- 0.5, respectively). These data indicate that, while endurance training significantly reduces the HR component of the arterial baroreflex, the arterial pressure response apparently is not altered.

Alpha 1-adrenergic coronary constriction during exercise and ischemia.

This paper reviews work primarily from our laboratories, examining an alpha 1-adrenergic receptor-mediated coronary constriction during exercise and myocardial ischemia in dogs. It was demonstrated that in the quiescent conscious dog, the coronary circulation is devoid of an alpha 1-coronary constriction. Furthermore, it was shown by the intracoronary injection of selective agonists that both alpha 1- and alpha 2-receptor subtypes are present in coronary vessels. However, during exercise or ischemia only the selective alpha 1-antagonist prazosin caused an increase in coronary inflow, indicating that only alpha 1-receptors were activated. During both conditions, the increase in flow caused by alpha 1-blockade was associated with an increased contractile function in subendocardium. In experiments on anesthetized dogs, it was shown that prazosin caused an equal increase in perfusion of subepicardial and subendocardial layers during stellate ganglion stimulation. However, contractile function was increased only in subendocardium. It was proposed that only in deeper muscle layers does an alpha 1-coronary constriction impose a flow-limitation on contractile function. Finally, recent results indicate that myocardial ischemia, produced either by partial coronary stenosis or by maintenance of coronary inflow at the resting level during exercise, may initiate a vicious cycle with a further increase in alpha 1-adrenergic coronary constriction. Abolition of this positive feedback mechanism may partially explain the anti-infarction effects of chronic ventricular sympathectomy, as previously observed in our laboratories.

Comparative effects of alpha-1 and alpha-2 adrenoceptors in modulation of coronary flow during exercise.

During submaximal exercise, an alpha adrenergic vasoconstriction that opposes metabolic dilation exists in the coronary circulation. Fifteen dogs were given i.c. injections of prazosin (0.5 mg) or yohimbine (0.7 mg) to determine the participation of alpha 1 and alpha 2 adrenoceptors in the vasoconstriction during exercise. All dogs were chronically instrumented to measure left circumflex blood flow, heart rate, regional left ventricular function and global left ventricular function. The experimental protocol consisted of a graded exercise regimen during which, at the highest level of exercise an alpha antagonist was given i.c. Exercise significantly increased heart rate, left ventricular pressure, dP/dt, systolic shortening and rate of shortening, and coronary blood flow. After the prazosin injection there was an increase in circumflex blood flow (25 +/- 3%) as well as regional (38 +/- 6%) and global (20 +/- 3%) contractile function. However, there was no change in circumflex blood flow or myocardial function after yohimbine. These data indicate that during exercise the sympathetic constrictor tone in the coronary circulation is mediated primarily by alpha 1 adrenoceptors, with little or no involvement from alpha 2 adrenoceptors.

Coronary and cardiac responses to exercise after chronic ventricular sympathectomy.

This study examined the effects of chronic surgical ventricular sympathectomy on the relationships between left ventricular mechanical performance, coronary blood flow, and exercise workload in sham-operated control dogs and dogs which had been ventricular sympathectomized 8 wk earlier. During exercise, left ventricular global contractile state was less in sympathectomized ventricles than in control ventricles, as indicated by reduced systolic pressure and maximal rate of pressure generation. Regional contractile shortening was not different. Heart rate was significantly elevated in sympathectomized ventricles. Therefore, peak systolic pressure-heart rate product and tension-time index were not different in sympathectomized ventricles compared to control ventricles. However, at each level of exercise, mean coronary flow in sympathectomized ventricles was reduced by about 50% compared to control values. The slopes of coronary flow on pressure-rate product and tension-time index were also reduced. No difference in left ventricular oxygen extraction between control and sympathectomized hearts were observed. Thus, chronic ventricular sympathectomy altered the relationships between coronary flow and oxygen consumption, on the one hand, and ventricular oxygen-dependent performance and whole-body exercise level, on the other hand.

Myocardial flow and function after regional beta-blockade in exercising dogs.

This study was designed to examine the contribution of beta 1- and beta 2-adrenergic receptors in modulating coronary blood flow and cardiac function in exercising dogs. Dogs were chronically instrumented to measure left circumflex flow velocity (CFV), heart rate, regional left ventricular function [systolic shortening, (%S) and maximum velocity of shortening (dL/dt(s)max)], and global left ventricular function [left ventricular pressure (LVP and dP/dtmax)]. Exercise significantly increased LVP (31 +/- 4%), dP/dtmax (130 +/- 17%), heart rate (116 +/- 20%), %S (28 +/- 6%), dL/dt(s)max (89 +/- 23%), and CFV (91 +/- 25%). Regional injection of the non-selective beta-blocker propranolol (1.0 mg) into the circumflex artery during exercise was associated with decreases in LVP (-8 +/- 3%), dP/dtmax (-17 +/- 3%), %S (-15 +/- 4), dL/dt(s)max (-13 +/- 4%), and CFV (-22 +/- 4%). Selective beta 1-receptor blockade with atenolol (1.0 mg, i.c.) was associated with similar decreases in LVP (-7 +/- 3%), dP/dtmax (-33 +/- 4%), %S (-12 +/- 3%), dL/dt(s)max (-17 +/- 2%), and CFV (-18 +/- 3%) during exercise. In contrast, selective beta 2-receptor blockade with ICI 118551 (250 micrograms, i.c.) produced significant decreases in only CFV (-11 +/- 2%) during exercise. Thus, the data suggest that the reductions in myocardial contractile function and flow after regional beta-blockade are primarily due to a decrease in myocardial beta 1-receptor stimulation. In addition, there apparently is a small involvement of either coronary vascular or pre-synaptic beta 2-receptors in mediating the coronary vascular flow response during exercise.