A Dissociation of Positive Staircase (Bowditch) from Ouabain-Induced Positive Inotropism

Abstract

The effects of verapamil on myocardial contractility were examined in perfused rabbit ventricular preparations. Verapamil (0.2 µ M ) decreased the time derivative of developed force (dF/dt) of the preparations paced at 90 beats/min to 39 ± 3% ( SE ) of the control value. Partial reversal to 76 ± 5% of the control value was achieved by subsequent perfusion with drug-free Krebs solution. Verapamil hastened the decline and delayed the return of contractility in response to a cycle of calcium washout and reperfusion. It converted the response to increased heart rate from positive (Bowditch effect) to negative inotropism. Moreover, the sensitivity to the drug was frequency related; the drug concentration required to induce a 50% decrease in dF/dt was an inverse function of heart rate, suggesting that the drug altered contractility by interfering with a phenomenon associated with systole. Verapamil did not decrease the magnitude of the positive inotropic response to 0.5 µ M ouabain, although a significant delay in the development of the response was observed. After 8 minutes of ouabain perfusion dF/dt had increased 35 ± 2% in the absence of verapamil but only 13 ± 1% in the presence of 1.0, µ M verapamil. The maximum response to ouabain was a 39 ± 4% increase at 9 minutes in the absence of verapamil and a 34 ± 2% increase at 23 minutes in the presence of verapamil. These results suggest that the responses to increased frequency and to cardiac glycosides are not explained by a common mechanism such as sodium-calcium exchange occurring during diastole or any other diastole-related mechanism for calcium influx. However, the possibility that both events are mediated by some common mechanism occurring during systole has not been eliminated.