Effect of nifedipine on cyclic GMP turnover in cultured coronary smooth muscle cells.
We investigated the effects of nifedipine on cyclic GMP turnover and the pertinent enzyme activities in cultured coronary smooth muscle cells (SMC). Nifedipine at high concentrations slightly decreased basal soluble guanylate cyclase activity and inhibited the action of sodium nitroprusside (SNP) but had no effect on the particulate form of the enzyme. In contrast, nifedipine inhibited cyclic GMP hydrolysis by directly inhibiting the partially purified calmodulin-stimulated isoform of phosphodiesterase (type I PDE) with IC50 of 4.2 microM. Nifedipine > or = 1.0 microM enhanced cyclic GMP accumulation in response to 1.0 microM SNP, although nifedipine alone exerted no influence on cyclic GMP levels. Enhancement of cyclic GMP accumulation by nifedipine in response to SNP was not affected by BAY K 8644, a calcium channel agonist. These properties may be shared by other dihydropyridines since nicardipine and nisoldipine also inhibited type I PDE with similar IC50. However, some other structurally unrelated calcium channel blockers, diltiazem and verapamil, had little effect on cyclic nucleotide hydrolysis or on cyclic GMP accumulation in response to SNP. Nifedipine may synergistically enhance cyclic GMP accumulation in response to nitric oxide (NO)-releasing agents by directly inhibiting type I PDE in coronary SMC. Such effects of nifedipine may partly contribute to coronary vasodilation and prevention of coronary spasm in patients with ischemic heart disease.
Kishi
Y
Y
Third Department of Medicine, Tokyo Medical and Dental University, Japan.
Watanabe
T
T
Makita
T
T
Sakita
S
S
Watanabe
R
R
Ashikaga
T
T
Numano
F
F
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006868:Hydrolysis; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D009543:Nifedipine