Stimulation of coronary vascular PGI2 by organic nitrates.
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.
D000818:Animals; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis; D014665:Vasodilator Agents / Q000494:pharmacology*
D009566:Nitrates; D013402:Sugar Alcohols; D014665:Vasodilator Agents; C030398:isosorbide-2-mononitrate; D013928:Thromboxane A2; C042286:teopranitol; D011464:Epoprostenol; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate