EFFECT OF NIFEDIPINE ON CYCLIC-GMP TURNOVER IN CULTURED CORONARY SMOOTH-MUSCLE CELLS

We investigated the effects of nifedipine on cyclic GMP turnover and t he pertinent enzyme activities in cultured coronary smooth muscle cell s (SMC). Nifedipine at high concentrations slightly decreased basal so luble guanylate cyclase activity and inhibited the action of sodium ni troprusside (SNP) but had no effect on the particulate form of the enz yme. In contrast, nifedipine inhibited cyclic GMP hydrolysis by direct ly inhibiting the partially purified calmodulin-stimulated isoform of phosphodiesterase (type I PDE) with IC50 of 4.2 mu M. Nifedipine great er than or equal to 1.0 mu M enhanced cyclic GMP accumulation in respo nse to 1.0 mu M SNP, although nifedipine alone exerted no influence on cyclic GMP levels. Enhancement of cyclic GMP accumulation by nifedipi ne in response to SNP was not affected by BAY K 8644, a calcium channe l agonist. These properties may be shared by other dihydropyridines si nce nicardipine and nisoldipine also inhibited type I PDE with similar IC50. However, some other structurally unrelated calcium channel bloc kers, diltiazem and verapamil, had little effect on cyclic nucleotide hydrolysis or on cyclic GMP accumulation in response to SNP. Nifedipin e may synergistically enhance cyclic GMP accumulation in response to n itric oxide (NO)-releasing agents by directly inhibiting type I PDE in coronary SMC. Such effects of nifedipine may partly contribute to cor onary vasodilation and prevention of coronary spasm in patients with i schemic heart disease.