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

Use of Verapamil

¹ Departments of Cell Biophysics and Medicine, Division of Myocardial Biology, Baylor College of Medicine, and the Fondren-Brown Cardiovascular Research and Training Center of the Methodist Hospital, Houston, Texas 77025

The effects of verapamil on myocardial contractility were examined in perfused rabbit ventricular preparations. Verapamil (0.2 µM) 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 µM 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, µM 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.

Submitted on October 22, 1973
Accepted on June 3, 1974

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