Cardiovascular effects of verapamil enantiomer combinations in conscious dogs

Abstract

We examined the systemic and coronary hemodynamic effects of five combinations of R- and S-verapamil enantiomers (R/S; 100/0, 90/10, 80/20, 50/50, and 20/80%, respectively) in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, coronary blood flow velocity, and aortic blood flow. Dogs received escalating doses (0.1, 0.2, and 0.4 mg kg⁻¹) of each verapamil combination over 2 min at 30 min intervals on different experimental days and peak changes in hemodynamics were recorded 2 min after each dose. All verapamil combinations increased heart rate, mean aortic blood flow, and coronary blood flow velocity and decreased calculated systemic and coronary vascular resistance. Alterations in coronary hemodynamics were most pronounced with 20/80 R/S verapamil. Racemic and 20/80 R/S verapamil decreased mean arterial and left ventricular systolic pressure, in contrast to combinations with greater concentrations of the R enantiomer. Left ventricular function was unchanged during administration of 100/0, 90/10, and 80/20 R/S verapamil. Direct negative inotropic and lusitropic effects occurred with 50/50 and 20/80 R/S verapamil. The high dose of 20/80 R/S verapamil also increased left ventricular end-diastolic pressure and the regional chamber stiffness constant, consistent with diastolic dysfunction. The results indicate that combinations of R- and S-verapamil produce differential hemodynamic and left ventricular functional effects in conscious, unsedated dogs that are dependent on the relative ratio of these enantiomers.

Introduction

The chirality of the calcium (Ca²⁺) channel antagonist verapamil confers important stereospecific differences in the cardiovascular actions of the optical isomers of the drug. Levo (−) verapamil produces negative chronotropic and inotropic effects, (Bayer et al., 1975b) delays atrioventricular node conduction, (Echizen et al., 1985; Echizen et al., 1988; Satoh et al., 1980) and causes systemic and coronary artery vasodilation (Satoh et al., 1980; Van Amsterdam and Zaagsma, 1988). In contrast, similar concentrations of dextro (+) verapamil produce vasodilation of the arterial and coronary vasculature but are relatively devoid of direct cardiac effects (Satoh et al., 1980; Van Amsterdam and Zaagsma, 1988). Commercially available verapamil consists of a racemic mixture of these optical isomers. The clinical efficacy of this drug has been widely demonstrated in the treatment of essential hypertension, supraventricular tachyarrhythmias, and ischemic heart disease (Aristizabal and Frohlich, 1994; Henry, 1980; Robertson and Robertson, 1996). The utility of racemic verapamil as an arterial and coronary vasodilator may be limited by the direct negative chronotropic, dromotropic, inotropic, and lusitropic (relaxation) effects of the drug, however (Walsh and O'Rourke, 1985). The present investigation examined the hypothesis that combinations of R- and S-verapamil [corresponding to the dextro (+) and levo (−) optical isomers, respectively] based primarily on the R-enantiomer preserve the beneficial vasodilator actions of this Ca²⁺ channel blocker without causing depression of myocardial contractility or left ventricular diastolic dysfunction. Conscious, unsedated dogs were used to allow direct comparison of the systemic and coronary hemodynamic actions and left ventricular functional effects of verapamil enantiomer mixtures in the same animal without the confounding influence of baseline anesthetics or acute surgical intervention.