POSSIBLE INVOLVEMENT OF NITRIC-OXIDE CGMP PATHWAY IN THE NEGATIVE CHRONOTROPIC EFFECT OF CD-832, A NOVEL DIHYDROPYRIDINE DERIVATIVE

Effects of zaprinast, an inhibitor of guanosine 3', 5'-cyclic monophos phate (cGMP)-specific phosphodiesterase, and methylene blue, an inhibi tor of soluble guanylate cyclase, on the negative chronotropic respons e to CD-832, a novel dihydropyridine derivative with a nitrate moiety, and nifedipine were examined with isolated guinea-pig right atria in the presence and absence of isoproterenol. CD-832 and nifedipine produ ced concentration-dependent negative chronotropic effects both in the absence and presence of isoproterenol. In the absence of isoploterenol , the concentration-response curves for CD-832 and nifedipine were nei ther potentiated by zaprinast nor inhibited by methylene blue. In the presence of isoproterenol (10(-8) M), zaprinast produced a three-fold leftward shift of the concentration-response curve for CD-832, while m ethylene blue produced a three-fold rightward shift. The concentration -response curve for nifedipine was not affected by these agents. SIN-1 , a nitric oxide (NO) donor, had no chronotropic effect in the absence of isoproterenol, but had a concentration-dependent negative chronotr opic effect in the presence of isoproterenol: the beating rate decreas ed to values close to that in the absence of isoproterenol. These find ings suggest that NO-cGMP mediated pathway is involved in the negative chronotropic actions of CD-832 under beta-adrenergic stimulation.