Shogen Isoyama

Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts.

Myocardial ischemia causes both systolic and diastolic dysfunction. A variety of positive inotropic agents with different subcellular mechanisms may be used clinically in an attempt to reverse ischemic contractile failure. We tested the hypothesis that two inotropic agents, isoproterenol (a β-adrenergic agonist) and ouabain (a sodium pump inhibitor), might have different effects on left ventricular (LV) diastolic function during ischemic failure despite an equivalent inotropic effect. Isolated isovolumk (balloon-in-LV) blood perfused rabbit hearts were paced at constant physiological heart rate (4 Hz), given either no drug (controls, n = 7), isoproterenol (n = 7), or ouabain (n = 7), and then subjected to 6 minutes of low flow ischemia (75% reduction of baseline coronary flow). The doses of isoproterenol and ouabain were selected to produce equivalent modest inotropic effects (15% increase in LV +dP/dt) in each heart during baseline perfusion conditions. During the ischemic period, there was a marked decrease in contractility, and neither isoproterenol nor ouabain demonstrated a positive inotropic effect relative to the control group. However, these agents had markedly different effects on diastolic chamber distensibility (assessed by end-diastolic pressure at constant LV volume) during ischemia. In the control and isoproterenol groups, diastolic chamber distensibility did not change during the ischemic period. In contrast, ouabain treatment resulted in a marked decrease in diastolic chamber distensibility during ischemia; this change was not completely reversible during the 10-minute reperfusion period. The mechanism by which ouabain decreased diastolic chamber distensibility relative to isoproterenol was assessed indirectly. The ouabain and isoproterenol groups were subjected to equivalent degrees of ischemia as assessed by oxygen supply/demand imbalance; during ischemia, each drug group did not differ with regard to myocardial perfusion rates, determinants of myocardial oxygen demand (heart rate, LV developed pressure, LV +dP/dt), myocardial oxygen consumption, lactate production, and ATP and creatine phosphate content. We therefore inferred that the greater decrease in diastolic distensibility in the ouabain group was not due to a greater metabolic severity of ischemia. These observations are consistent with a mechanism of cytosolic calcium overload induced by ouabain, resulting in persistent active myofilament tension development throughout diastole, to cause the observed decrease in diastolic chamber distensibility during ischemia in the ouabain group. Regardless of the subcellular mechanism, the results suggest that digitalis glycosides may have deleterious effects on diastolic function during low flow ischemia. (Circulation Research 1988;63:457–467)

Acute decrease in left ventricular diastolic chamber distensibility during simulated angina in isolated hearts.

It is not clear what factors contribute to the prompt and reversible decrease in left ventricular diastolic chamber distensibility during angina pectoris that is induced by an increase in myocardial energy demand due to exercise or pacing tachycardia. To simulate the demand ischemia that occurs clinically during pacing-induced angina, we used isolated, blood-perfused rabbit hearts with restricted coronary flow and increased myocardial energy demand. A constant left ventricular balloon volume model was used to measure left ventricular diastolic chamber distensibility during 6 minutes of low-flow global ischemia, induced by a reduction in coronary perfusion pressure from 100 to 20 mm Hg. To investigate the influence of different levels of myocardial energy demand, the effects of two different heart rates were studied during low-flow global ischemia; pacing tachycardia (6.4 ± 0.2 Hz, n = 7) was compared with the rabbits baseline heart rate of 4 Hz (n = 7). Low-flow ischemia caused a marked decrease in contractile function relative to the baseline preischemic state. In the pacing-tachycardia group, myocardial energy demand, as estimated by the rate ± systolic pressure product, was significantly greater than in the constant heart-rate group. When tachycardia was imposed during low-flow global ischemia, there was a transient and reversible increase in isovolumic left ventricular end-diastolic pressure from 14 ± 1 to 25 ± 4 mm Hg (measured during long diastoles obtained with transient cessation of pacing) in the pacing-tachycardia group, but there was no increase in left ventricular end-diastolic pressure during low flow ischemia in the constant heart-rate group with lower energy demand (p<0.01). The time constant of left ventricular relaxation also markedly increased in low-flow ischemia combined with pacing tachycardia. Glycolytic flux (as estimated by coronary venous-arterial lactate concentration difference) increased during low-flow ischemia at the baseline heart rate of 4 Hz but did not increase further during the elevated energy demand of pacing tachycardia. We conclude that in isolated, blood-perfused hearts, global myocardial ischemia due to a reduction in coronary flow alone is not associated with a decrease in diastolic chamber distensibility. However, when a pacing-induced increase in myocardial energy demand is superimposed on the ischemic myocardium and exceeds its capacity to generate high-energy phosphates, a rapid and reversible decrease in left ventricular diastolic chamber distensibility develops similar to that which occurs in response to pacing-induced angina in humans. This finding in isolated, blood-perfused hearts with global ischemia supports the hypothesis that the increase in left ventricular diastolic pressure that occurs during angina in humans is related to the effects of demand ischemia on myocardial relaxation per se and does not require dyssynchronous contraction of ischemic and nonischemic segments, nor does it depend on pericardial or right ventricular factors.

Reversal of Coronary Circulation Abnormalities After Relief of Pressure Overload in the Rat

We tested the hypothesis that impaired coronary autoregulation and decreased coronary flow reserve in hypertrophied hearts may regress after relief of pressure overload. We banded the ascending aortas of Wistar rats for 4 weeks. Debanding was then performed on some of these banded rats. Four weeks after banding or debanding, the chest was opened and in vivo left ventricular pressure was measured. The heart was isolated and perfused with Tyrode’s solution containing bovine red blood cells (Ht, 30%) and serum albumin (15 g/1). The perfusate was oxygenated with a gas mixture containing 20% O2, 3% CO2, and 77% N2. The left ventricular cavity was kept empty. Coronary perfusion pressure-flow relationships were obtained over a range of coronary perfusion pressures between 25 and 175 mmHg. Reactive hyperemic response was estimated after 40-s ischemia at 50, 100, and 150 mmHg perfusion pressure. In vivo peak systolic left ventricular pressure increased to 178 ± 8 mmHg in the hearts of the banded group (103 ± 6 in the hearts of sham-operated rats). The increased pressure produced significant myocardial hypertrophy (3.51 ± 0.16 vs 2.41 ± 0.05 mg/g heart weight/body weight ratio). After debanding, peak systolic left ventricular pressure decreased to the control level, and myocardial hypertrophy regressed to 15% above the control value. Coronary autoregulation was observed in control hearts, but was impaired in the hearts of the banded group over the whole range of perfusion pressures.