Abstract
In the retrogradely perfused, paced rat heart, we studied the effects of the stereoisomers of verapamil (VER), gallopamil (GAL), devapamil (DEV) and bepridil (BEP) on the coronary flow and the maximum systolic left ventricular pressure (MSLVP). In addition, the time courses of onset and recovery of these effects were measured. The verapamil analogues showed high stereoselectivity factors (sf) for MSLVP depression in favour of the (-)-enantiomers and low sf's for coronary flow increase. Bepridil showed a low sf for both parameters with the (+)-enantiomer being more potent. In a previous study we found that in the rat heart, dihydropyridine calcium antagonists clearly possess high selectivity for the vascular isochannel site as compared to the myocardial site, whereas racemic verapamil derivatives were devoid of such selectivity. In the present study the (+)-enantiomers of all verapamil congeners revealed a marked vasoselectivity. This was not found for the (-)-isomers, which surprisingly were virtually equipotent for MSLV depression and coronary flow increase, suggesting a different voltage dependence of the two isochannel verapamil sites for the enantiomers of verapamil and its congeners. Onset and offset velocities were clearly different as well. The kinetics of coronary flow increase were identical and fast for all enantiomers studied. MSLV kinetics were slower. In particular the recovery was markedly different for the enantiomers of each drug, the more potent isomer having the lower velocity. Furthermore, the differences in recovery of MSLVP depression between the verapamil type enantiomers suggest that the recovery rate may directly reflect dissociation from the myocardial isochannel verapamil site.
Published Version
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