Holzmann S, Kukovetz W R, Braida C, Pöch G
Department of Pharmacology and Toxicology, Universitätsplatz 2, Graz, Austria.
Eur J Pharmacol. 1992 Apr 29;215(1):1-7. doi: 10.1016/0014-2999(92)90600-9.
The relaxant effect of the vasodilator drug, nicorandil, was studied in circular strips of bovine coronary arteries. To differentiate between relaxation caused by cyclic GMP (cGMP) and by hyperpolarization, the influence of cGMP was blocked with methylene blue and that of hyperpolarization with the inhibitor of ATP-dependent K+ channels, glibenclamide. Methylene blue and glibenclamide inhibited nicorandil-induced relaxation to similar extents. Cromakalim-induced relaxation but not that due to sodium nitroprusside (nitroprusside-Na) was inhibited by glibenclamide. Methylene blue inhibited the relaxation caused by nitroprusside-Na but not that due to cromakalim. The different modes of action of the two components of relaxation caused by nicorandil were studied in agonist-agonist interaction experiments. The interaction between nicorandil and nitroprusside-Na or 3-morpholino-sydnonimine (SIN-1) was overadditive in the absence of glibenclamide but additive, i.e. competitive, in the presence of glibenclamide. The interaction of nicorandil with cromakalim or pinacidil was overadditive in the absence of methylene blue but additive, i.e. competitive, in the presence of methylene blue. The results show that nicorandil relaxes smooth muscle through two independent mechanisms: ATP-dependent activation of K+ channels and stimulation of guanylyl cyclase resulting in increases in cGMP.
在牛冠状动脉环形条带中研究了血管扩张剂尼可地尔的舒张作用。为了区分由环磷酸鸟苷（cGMP）引起的舒张和超极化引起的舒张，用亚甲蓝阻断cGMP的影响，并用ATP依赖性钾通道抑制剂格列本脲阻断超极化的影响。亚甲蓝和格列本脲对尼可地尔诱导的舒张的抑制程度相似。格列本脲抑制了克罗卡林诱导的舒张，但不抑制硝普钠（硝普钠-Na）诱导的舒张。亚甲蓝抑制硝普钠-Na引起的舒张，但不抑制克罗卡林引起的舒张。在激动剂-激动剂相互作用实验中研究了尼可地尔引起的两种舒张成分的不同作用方式。在不存在格列本脲的情况下，尼可地尔与硝普钠-Na或3-吗啉代西多胺（SIN-1）之间的相互作用是超相加性的，但在存在格列本脲的情况下是相加性的，即竞争性的。在不存在亚甲蓝的情况下，尼可地尔与克罗卡林或吡那地尔的相互作用是超相加性的，但在存在亚甲蓝的情况下是相加性的，即竞争性的。结果表明，尼可地尔通过两种独立的机制使平滑肌舒张：ATP依赖性激活钾通道和刺激鸟苷酸环化酶导致cGMP增加。
