QUINIDINE-INDUCED POTENTIATION OF CARDIOVASCULAR EFFECTS OF NITRENDIPINE - FUNCTIONAL-ASPECTS AND POSSIBLE MOLECULAR MECHANISMS

The functional interaction between the dihydropyridine calcium channel blocker nitrendipine and quinidine was studied in isolated preparatio ns from guinea-pig cardiac ventricle and in mesenteric arterial segmen ts under a variety of experimental conditions. The negative inotropic potency of nitrendipine is clearly enhanced by quinidine (3 . 10(-6)-1 0(-4) mol/l) by up to two orders of magnitude, i.e. cardiac nitrendipi ne effects are potentiated. Vasorelaxant effects, however, remain larg ely unaffected (nitrendipine potency is increased by half an order of magnitude maximally). To elucidate the mechanism of this interaction, the ability of quinidine to potentiate the negative inotropic effect o f a series of 12 dihydropyridines was compared with their voltage-depe ndence of action in guinea-pig left atria. No significant correlation is found (r = 0.18). Furthermore, quinidine inhibits rather than stimu lates binding of tritiated nitrendipine, nimodipine or (S)-isradipine to isolated cardiac membranes. Therefore, the mechanism of the quinidi ne-nitrendipine interaction differs from those previously proposed for modulation of dihydropyridine binding by other drugs. We hypothesize that quinidine-occupied calcium channels adopt an intermediate affinit y for nitrendipine, higher than in resting channels, but lower than th e high affinity present with inactivated channels. Model calculations which are based on this assumption are able to reproduce all experimen tal findings of this study.