Cellular action of nicardipine.
Nicardipine, a calcium antagonist of the 1:4 dihydropyridine type, has been used to treat angina and hypertension and is currently being examined as an agent for treating ischemia of cerebral and myocardial tissue. Nicardipine shows high affinity for the dihydropyridine binding site (pKi = 9.7) and inhibits the L-type calcium ion channel as demonstrated by its ability to decrease the calcium ion-dependent action potential dose-dependently in ventricular papillary muscle (pIC50 = 7.15). Nicardipine shows greater potency in inhibiting the response of vascular smooth muscle (pIC50 = 8.20) than that of cardiac muscle (pIC50 = 7.15). The nicardipine selectivity for vascular smooth muscle is greater than that shown by other dihydropyridine calcium antagonists such as nifedipine and accounts for the efficacy of nicardipine in the treatment of angina and hypertension. Various mechanisms have been proposed to account for the beneficial action of nicardipine in treating animal models of cerebral ischemia and myocardial infarction. For example, it has been suggested that (1) nicardipine has a specific membrane-stabilizing effect on cell membranes, (2) the compound blocks certain sodium channels, (3) it may become concentrated in ischemic cells, or (4) it may stimulate calcium ion efflux from mitochondria, and these actions may account for the inhibition by nicardipine of veratrine-induced contraction of myocytes. In this study, some of these effects of nicardipine were examined. However, the suggestion that nicardipine concentrates in ischemic cells owing to the tertiary amine structure could not be conclusively demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Michel
A D
AD
Institute of Pharmacology, Syntex Research, Palo Alto, California.
Whiting
R L
RL
D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D009529:Nicardipine / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000378:metabolism*; D014316:Tritium
D014316:Tritium; D009529:Nicardipine