Schrör K, Ahland B, Weiss P, König E
Institut für Pharmakologie, Universität Düsseldorf, F.R.G.
Eur Heart J. 1988 Jan;9 Suppl A:25-32. doi: 10.1093/eurheartj/9.suppl_a.25.
The present study summarizes recent investigations in our laboratory, demonstrating that a number of organic nitrates, including glyceryltrinitrate, isosorbide dinitrate, isosorbide-2-mononitrate and the novel nitrate teopranitol stimulate the release of a prostacyclin (PGI2)-like antiplatelet activity from isolated bovine coronary arteries and veins. In bioassay experiments this increase amounted to 50 to 200% of control. Evidence for nitrate induced PGI2 stimulation is presented by inhibition of its formation by indomethacin and dexamethasone, the demonstration of inhibition of thrombin induced thromboxane generation of washed platelet suspensions by nitrate stimulated vessel incubates and an enhanced accumulation of the hydrolysis product of PGI2, 6-oxo-PGF1 alpha, in incubates of teopranitol stimulated vessels. This action is obtained at nanomolar, i.e. therapeutic concentrations of the compounds and requires the presence of free nitro group(s) at [exo] position of the isohexide molecule. There was no correlation between PGI2 release and the relaxing action of the nitrates on isolated vessel strips. The inhibitor of cyclic GMP accumulation, methylene-blue, also blocked the generation of the antiplatelet activity by glyceryltrinitrate and teopranitol. Recent evidence suggests that cGMP accumulation via intermediate nitrogen oxide (NO) production mediates the vascular effects of organic nitrates. Since NO is also a potent antiplatelet agent, it is concluded that a nitrate stimulated PGI2 release associated with or mediated by NO formation might explain the antiplatelet actions of organic nitrates in vitro and ex vivo.
本研究总结了我们实验室最近的研究，表明包括硝酸甘油、异山梨醇二硝酸酯、异山梨醇 -2- 单硝酸酯和新型硝酸盐替普拉尼醇在内的多种有机硝酸盐，可刺激离体牛冠状动脉和静脉释放一种类似前列环素（PGI2）的抗血小板活性物质。在生物测定实验中，这种增加量相当于对照的 50% 至 200%。硝酸酯诱导的 PGI2 刺激的证据如下：吲哚美辛和地塞米松抑制其形成；硝酸酯刺激的血管孵育物抑制凝血酶诱导的洗涤血小板悬液中血栓素的生成；替普拉尼醇刺激的血管孵育物中 PGI2 的水解产物 6- 氧代 -PGF1α 的积累增加。这种作用在纳摩尔浓度下即可获得，即这些化合物的治疗浓度，并且需要异山梨醇分子的 [外] 位存在游离硝基。PGI2 的释放与硝酸盐对离体血管条的舒张作用之间没有相关性。环鸟苷酸（cGMP）积累的抑制剂亚甲蓝也可阻断硝酸甘油和替普拉尼醇产生抗血小板活性。最近的证据表明，通过中间产物一氧化氮（NO）的产生导致的 cGMP 积累介导了有机硝酸盐的血管效应。由于 NO 也是一种有效的抗血小板剂，因此可以得出结论，与 NO 形成相关或由其介导的硝酸盐刺激的 PGI2 释放可能解释了有机硝酸盐在体外和体内的抗血小板作用。
