Cellular action of nicardipine

Abstract

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. Nicardipne shows high affinity for the dihydropyridine binding site (pK i = 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 (pIC 50 = 7.15). Hicardipine shows greater potency in inhibiting the response of vascular smooth muscle (plC 50 = 8.20) than that of cardiac muscle (piC 50 = 7.15). The nicardipine selectivity for vascular smooth muscle is greater than that shown by other d1hydropyrtdine 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. The membrane-stabilizing activity of nicardipine, probably related to the highly lipophilic nature of the molecule, appears responsible for the efficacy of nicardipine in animal models of myocardial infarction and cerebral ischemia. Other less liphophilic dihydropyridine calcium antagonists do not possess such activity.