The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis.
We studied the action of the biologically active metabolite of molsidomine, N-morpholino-N-nitrosoamino-acetonitrile (SIN), on eicosanoid formation and functional behavior of bovine coronary arteries and human platelets in vitro. Glyceryltrinitrate (GTN) and prostaglandin (PG) I2 were used as reference compounds. SIN dose-dependently inhibited the thrombin-, collagen-, and primary ADP-induced platelet aggregation. The IC50 was in the range of 0.1-0.8 mumol/L. At these concentrations SIN also inhibited thromboxane formation, but did not influence the PGI2 biosynthesis of coronary vessels. Molsidomine itself was inactive. GTN stimulated vascular PGI2 formation, but did not modify the platelet aggregation at comparable concentrations. A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN. The IC50 amounted to 1.7 +/- 0.4 mumol/L and was in the same range as with 5,8,11,14-eicosatetraynoic acid (2.0 +/- 0.3 mumol/L). Although the results may not suggest a common mechanism of the antiaggregatory action of GTN and SIN, they provide no evidence of a similar or dissimilar mechanism of action in vascular smooth muscle.
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects*; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015289:Leukotrienes; D008981:Molsidomine / Q000031:analogs & derivatives; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D005996:Nitroglycerin / Q000494:pharmacology; D009602:Nitrosamines / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D013558:Sydnones / Q000494:pharmacology*; D013931:Thromboxanes / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D015289:Leukotrienes; D009602:Nitrosamines; D010069:Oxadiazoles; D013558:Sydnones; D013931:Thromboxanes; D014665:Vasodilator Agents; C006006:N-nitrosomorpholinoaminoacetonitrile; C002385:linsidomine; C021201:12-HPETE; D008981:Molsidomine; D011464:Epoprostenol; D005996:Nitroglycerin