Nitric oxide-mediated cyclooxygenase activation - A key event in the antiplatelet effects of nitrovasodilators

We have evaluated the contributions of nitric oxide (NO) and prostacyclin (PGI(2)) in the in vivo antiplatelet effects of clinically useful nitrovasodilators. In rats, intravenous infusion of three NO donors, glyceryl trinitrate, sodium nitroprusside, or 3'-morpholinosydnonimine, the stable metabolite of molsidomine, released 6-keto PGF1 alpha (the stable metabolite of PGI(2)) and inhibited ex vivo human platelet aggregation to adenosine diphosphate by at least 80%, In in vitro studies, glyceryl trinitrate, sodium nitroprusside, and 3'-morpholinosydnonimine, at clinically attainable concentrations, increased cyclooxygenase activity in endothelial cells (EC), which resulted in a four- to sixfold release of 6-keto PGF1 alpha. Pretreatment of the EC with hemoglobin which binds to and inactivates the biological actions of NO, hut not by methylene blue (MeB), attenuated the NO-mediated PGI(2) from the EC by at least 70%, Release of 6-keto PGF1 alpha by the NO donors increased the ability of these compounds to inhibit thrombin-induced human platelet aggregation by at least 10 times; this potentiation was inhibited by hemoglobin but not by MeB, MeB blocked the direct antiplatelet effect of the NO donors in the absence of EC. In summary, we have demonstrated that NO, directly as well as together with an NO-driven cyclooxygenase activation (and hence PGI(2)), release contributes to the marked antiplatelet effects observed after the in vivo administration of clinically used nitrovasodilators.