Diminished toxicity of ouabain in the hypertrophied rat heart

The responsiveness to ouabain of hypertrophied rat hearts has been investigated either in vivo using an isolated Langendorff rat heart perfused at various external calcium concentrations, or in vitro on purified sarcolemma vesicles. (i) The physiological study shows that at 0.25 mM CaCl2, the positive inotropic effect of 10(-5) M ouabain was diminished in hypertrophied hearts (p less than 0.02). At 0.5 mM CaCl2, the drug has no effect in controls, but it has a slight positive inotropic effect in hypertrophied hearts. At 2.50 mM CaCl2, ouabain has a negative inotropic effect accompanied by extrasystoles in controls, but in hypertrophied hearts it still has a positive inotropic effect and is not arrhythmogenic. (ii) After the pretreatment of the hearts with 2.5 mM CaCl2, the responsiveness of the (Na+, K+)-ATPase activity to ouabain was studied: the sarcolemma from hypertrophied heart contains half as many low affinity forms of (Na+, K+)-ATPase for ouabain (35% +/- 6) than in controls (80% +/- 2). Assuming that the low affinity forms are responsible for the toxic effect, these data correlate well with some of the physiological findings and suggest that the diminished toxicity for ouabain in hypertrophied hearts rather reflects a modification of the properties of the (Na+, K+)-ATPases than a change in the myocardial calcium metabolism.