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.
Sun
J
J
School of Pharmacy, State University of New York, Buffalo, USA.
Triggle
D J
DJ
D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D002121:Calcium Channel Blockers; D014316:Tritium