Calcium channel antagonists: Cardiovascular selectivity of action

The activities of a series of calcium antagonists including nifedipine, verapamil, diltiazem and second-generation 1,4- dihydropyridines were determined in isolated vascular and cardiac preparations by tissue pharmacology and radioligand binding methods. The inhibitory effects against responses induced by 80 mM K⁺ depolarization in rat tail artery and against contractions evoked in electrically paced rat papillary muscle were determined. Comparison of these IC₅₀ values defines a vascular/cardiac ratio as an index of relative activities in these tissues. Competition studies of the 1,4-dihydropyridines with [³H]PN 200 110 binding in neonatal rat myocytes under polarized (5.8 mM K⁺) and depolarized (50 mM K⁺) states yields an index of voltage-dependent binding. The 1,4-dihydropyridine calcium antagonists exhibit significantly higher vascular/cardiac ratios (31-877) than do the nondihydropyridines (1.9-2.1); with the exception of amlodipine, the second-generation 1,4-dihydropyridines have a higher vascular selectivity than the first-generation nifedipine. The ratios of voltage-dependent binding and vascular selectivity correlate well, consistent with a relationship between the two processes. A similar relationship is also observed in a small series of amlodipine derivatives bearing heterocyclic substituents at the 2- position of the 1,4-dihydropyridine ring. These results suggest that calcium antagonists, especially the 1,4-dihydropyridines do show different degrees of vascular selectivity and that voltage-dependent binding, influenced by chemical structure, is a major, but probably not exclusive, determinant of this selectivity.