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
beta-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 isovolumic (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.(ABSTRACT TRUNCATED AT 400 WORDS)