Cardiovascular effects of verapamil enantiomer combinations in conscious dogs
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.
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Methods
All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. All procedures conformed to the `Guiding Principles in the Care and Use of Animals' of the American Physiological Society and were performed in accordance with the `Guide for the Care and Use of Laboratory Animals,' [DHEW (DHHS) publication (NIH) no. 85-23, revised 1996].
Results
No differences in baseline systemic and coronary hemodynamics or indices of left ventricular function were observed between experimental groups during control conditions. R-verapamil caused significant (P<0.05) increases in heart rate, rate–pressure product, pressure–work index, mean aortic blood flow, and diastolic and mean coronary blood flow velocity (Table 1). Reductions in systemic vascular resistance and diastolic and mean coronary vascular resistance were observed with R-verapamil
Discussion
The present results indicate that combinations of R- and S-verapamil produce systemic and coronary hemodynamic effects in conscious, unsedated dogs that reflect a mixture of the cardiovascular actions of these enantiomers alone. All five combinations of R- and S-verapamil caused increases in heart rate that were probably mediated by baroreceptor reflex activation secondary to peripheral vasodilation. These findings support previous observations with racemic verapamil in conscious dogs (Millard
Acknowledgements
This work was supported in part by US PHS grant HL 54820 and Anesthesiology Research Training Grant GM 08377. The authors thank Dave Schwabe and John Tessmer for technical assistance and G.D. Searle, St. Louis, MO for the generous supply of R- and S-verapamil.
References (32)
- et al.
Comparative effects of bepridil and verapamil on isolated coronary and systemic vascular and cardiac muscle
Eur. J. Pharmacol.
(1982) - et al.
The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans
Am. Heart J.
(1985) Comparative pharmacology of calcium antagonists: nifedipine, verapamil and diltiazem
Am. J. Cardiol.
(1980)- et al.
Comparative electrophysiologic and coronary hemodynamic effects of diltiazem, nisoldipine and verapamil on myocardial tissue
Am. J. Cardiol.
(1982) - et al.
Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms
Am. J. Cardiol.
(1982) - et al.
Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance
Am. J. Cardiol.
(1990) - et al.
Effects of intravenous verapamil on hemodynamics in patients with heart disease
Am. Heart J.
(1977) - et al.
Effect of verapamil on left ventricular function: a randomized, placebo-controlled study
Am. J. Cardiol.
(1983) - et al.
Differential effects of systemic and intracoronary calcium channel blocking agents on global and regional left ventricular function in conscious dogs
Am. Heart J.
(1981) - Aristizabal, D., Frohlich, E.D., 1994. Calcium antagonists. In: Singh, B.N., Dzau, V.J., Vanhoutte, P.M., Woosley, R.L....