Kishi Y, Watanabe T, Makita T, Sakita S, Watanabe R, Ashikaga T, Numano F
Third Department of Medicine, Tokyo Medical and Dental University, Japan.
J Cardiovasc Pharmacol. 1995 Oct;26(4):590-5. doi: 10.1097/00005344-199510000-00013.
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.
我们研究了硝苯地平对培养的冠状动脉平滑肌细胞（SMC）中环鸟苷酸（cGMP）代谢及相关酶活性的影响。高浓度硝苯地平可轻微降低基础可溶性鸟苷酸环化酶活性，并抑制硝普钠（SNP）的作用，但对该酶的颗粒形式无影响。相反，硝苯地平通过直接抑制部分纯化的钙调蛋白刺激的磷酸二酯酶同工型（I型磷酸二酯酶）来抑制cGMP水解，其半数抑制浓度（IC50）为4.2微摩尔。硝苯地平≥1.0微摩尔时可增强对1.0微摩尔SNP的cGMP积累反应，尽管硝苯地平单独作用时对cGMP水平无影响。硝苯地平对SNP诱导的cGMP积累的增强作用不受钙通道激动剂BAY K 8644的影响。其他二氢吡啶类药物可能也具有这些特性，因为尼卡地平和尼索地平也以相似的IC50抑制I型磷酸二酯酶。然而，其他一些结构不相关的钙通道阻滞剂，如地尔硫䓬和维拉帕米，对环核苷酸水解或对SNP诱导的cGMP积累几乎没有影响。硝苯地平可能通过直接抑制冠状动脉SMC中的I型磷酸二酯酶，协同增强对一氧化氮（NO）释放剂的cGMP积累反应。硝苯地平的这种作用可能部分有助于冠心病患者的冠状动脉舒张和预防冠状动脉痉挛。
