Patricia Gwirtz

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.

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.

Chronic Sympathectomy of Canine Cardiac Ventricles Affects Gs-adenylyl Cyclase Coupling and Muscarinic Receptor Density

The effect of chronic ventricular sympathectomy on sarcolemmal muscarinic receptor (MR) and beta-adrenoceptor densities and coupling of these receptors to adenylyl cyclase was examined. Microsomal membranes were isolated from right and left ventricles of control dogs (sham- and nonoperated) and dogs with ventricles sympathectomized 4 weeks earlier. Relative to control membranes, MR density was decreased in left but not right ventricular (LV, RV) membranes from sympathectomized hearts. Relative carbachol inhibition of adenylyl cyclase was similar in RV and LV membranes from both heart groups, however, Although beta-adrenoceptor densities and ratio of beta 1- and beta 2-adrenoceptor subtypes did not change, basal adenylyl cyclase activity was 40% less in sympathectomized membranes as compared with control membranes. Furthermore, relative stimulation of adenylyl cyclase by isoproterenol was twofold greater in sympathectomized heart membranes. Because maximally stimulated adenylyl cyclase activity by NaF or MnCl2 was identical in sympathectomized and control membranes, the reduction in basal activity may not be related to a decrease in Gs and adenylyl cyclase. In support of this hypothesis, Gs alpha content as estimated from optimal cholera toxin-catalyzed ADP-ribosylation was similar in control and sympathectomized membranes. Therefore, an alteration in Gs interaction with adenylyl cyclase may account for the reduction in basal adenylyl cyclase activity and the increased relative responsiveness of adenylyl cyclase to isoproterenol in chronically sympathectomized ventricular membranes.

Computer analysis of cardiovascular parameters

A computer program is described for the analysis of several cardiovascular parameters frequently measured or derived in the chronically instrumented dog model. Data are stored on magnetic tape and are subsequently analyzed with the Apple IIe microcomputer equipped with the ADALAB (Interactive Microware, Inc.) analog-to-digital convertor. Not limited to the chronically instrumented animal model, the program is capable of analyzing left ventricular pressure, three channels of regional myocardial segment length, coronary flow velocity as measured by the Doppler ultrasonic flow technique, and two channels of systemic arterial pressure. Derived data include: left ventricular dP/dtmax, left ventricular pressure-heart rate product, left ventricular ejection time, tension time index; percent segment length shortening and velocity of shortening, dL/dt(s)max, regional stroke work and power, duration of systole and diastole; mean coronary flow velocity, peak diastolic and systolic flow velocity, and true mean systemic arterial pressure.

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.

α1-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.