Calcium Antagonistic Activity and Myocardial Ischemic Protection by Both Stereoisomers of Verapamil

Abstract

The effects of the optical isomers of verapamil were compared on intact and partially ischemic pig hearts as well as on vascular smooth muscle of rabbits and rats. In K+-depolarized strips of rabbit mesenteric artery, both isomers shifted calcium dose-response curves (tension development) in a qualitatively similar manner to the right, with threshold concentrations of 10–8 m (—)verapamil and 10–7 m (+)verapamil. In K+-depolarized rat aortic strips, the calcium antagonistic activity was quantified. (+)Verapamil was at least as potent as several other coronary drugs [(±)verapamil = 1]: perhexiline 0.02, prenylamine 0.05, fendiline 0.05, diltiazem 0.15, (±)verapamil 0.15, (-)verapamil 1.5. The optical isomers of D600 showed a considerably greater difference in calcium antagonistic potency (about a factor of 60) as compared to verapamil (factor of 10). In the pig heart, reversible and reproducible ischemia reactions were provoked by repeated occlusions (3 min) of a branch of the LAD followed by reperfusion for 15 min. In the tested range of 0.4–2.0 mg/kg i.V., (-I-)verapamil dose-dependently reduced ischemic ST elevations in four epicardial leads. At an intermediate dose of 1 mg/kg, (+Verapamil diminished ST-elevations by 32% (occlusion 11 min p.i.). Results not statistically different were obtained with 0.1 mg/kg (-)verapamil (28%) and 0.2 mg/kg (±)verapamil (40%). No qualitative differences between the isomers could be observed with regard to hemodynamic parameters with equieffective reduction of the ischemia reaction: slight decrease in heart rate; prolongation of PQ duration with only minimal and insignificant effect of (+)verapamil; decrease of systolic and diastolic blood pressure, left ventricular pressure, and LV dp/dt _max . In contrast to optically active and racemic verapamil, nifedipine in a hypotensive dose (0.05 mg/kg i.v.) increased heart rate and diminished ischemic ST elevations only moderately (13%). The results obtained on vascular smooth muscle and ischemic pig heart clearly show that there are no remarkable qualitative differences between verapamil enantiomers. It can be concluded that (+)verapamil, by its calcium antagonistic properties, contributes to the therapeutic efficacy of the racemic drug.