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 preparations from guinea-pig cardiac ventricle and in mesenteric arterial segments under a variety of experimental conditions. The negative inotropic potency of nitrendipine is clearly enhanced by quinidine (3 x 10(-6)-10(-4) mol/l) by up to two orders of magnitude, i.e. cardiac nitrendipine effects are potentiated. Vasorelaxant effects, however, remain largely 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 of a series of 12 dihydropyridines was compared with their voltage-dependence of action in guinea-pig left atria. No significant correlation is found (r = 0.18). Furthermore, quinidine inhibits rather than stimulates binding of tritiated nitrendipine, nimodipine or (S)-isradipine to isolated cardiac membranes. Therefore, the mechanism of the quinidine-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 affinity for nitrendipine, higher than in resting channels, but lower than the high affinity present with inactivated channels. Model calculations which are based on this assumption are able to reproduce all experimental findings of this study.
Herzig
S
S
Department of Pharmacology, University of Kiel, Germany.
Jischa
J
J
Beinhauer
A
A
Geirhos
B
B
Tacke
K
K
Hempelmann
R G
RG
D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004095:Dihydropyridines / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009568:Nitrendipine; D011803:Quinine