Verapamil-induced changes in myocardial contractile force and cyclic nucleotides in the isolated perfused rat heart

Abstract

Interrelationships among transmembrane flux of calcium ions, cyclic nucleotides, and myocardial contractile force in isolated, perfused rat hearts were studied with verapamil, lanthanum, or zero-calcium solutions to reduce the influx of calcium ions into myocardial cells. Myocardial concentrations of cyclic AMP and cyclic GMP were determined, and changes in contractile force were measured. Perfusion with verapamil, lanthanum, or zero-calcium solutions produced a dose-related decrease in myocardial contractile force and reduced cyclic AMP to levels significantly lower than in control hearts. The reduction in cyclic AMP was independent of the amount of drug used to inhibit calcium influx. Verapamil (6 × 10 −8 M) or lanthanum (4 × 10 −7 M or 4 × 10 −6 M) had no effect on the concentration of cyclic GMP. Zero-calcium solution or verapamil (6 × 10 −7 M) decreased significantly myoeardial cyclic GMP. 8-Bromo-cyclic GMP (in the presence of inorganic phosphate) and dibutyryl cyclic AMP caused a positive inotropic response which was not inhibited by sotalol. Only dibutyryl cyclic AMP reversed the negative inotropic effect of verapamil. Dibutyryl cyclic GMP alone produced a negative inotropic effect and further depressed the force of contraction induced by verapamil. Since two analogs of cyclic GMP had opposite effects on myocardial contractility, it was concluded that analogs do not necessarily mimic actions ascribed to endogenous parent nucleotides. Although the transmembrane flux of calcium ions remains an important factor controlling myocardial contractile force, the direct mechanism by which cyclic nucleotides may modulate calcium flux in the heart remains unknown.