Incubation of platelet-rich plasma with 80 microM aspirin that resulted in the inhibition of both the secondary phase of ADP induced platelet aggregation and prostaglandin synthesis simultaneously stimulated the production of NO in platelets. Furthermore it was found that the treatment of platelet-rich plasma either with 80 microM ibuprofen or salicylic acid, like aspirin, which inhibited the secondary phase of platelet aggregation by ADP and prostaglandin synthesis, also stimulated the production of NO in the absence of added ADP. However the inhibition of prostaglandin synthesis by ibuprofen or salicylic acid, unlike aspirin, was transient in nature. Incubation of washed platelets with any of these three compounds also stimulated NO synthesis indicating that the effect of these compounds was not mediated through plasma proteins. The in vitro effect of aspirin on the increase of NO in platelets could also be demonstrated by in vivo exposure of platelets to the compound. It was concluded that either a temporary or a lasting inhibition of prostaglandin synthesis by these inhibitors resulted in the synthesis of NO in resting platelets. Since NO is a potent inhibitor of platelet aggregation the inhibition of platelet aggregation, by these compounds may not be the consequence of the inhibition of prostaglandin synthesis alone, but could also be related, at least partly, to the stimulated synthesis of NO by these inhibitors.

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Aspirin, a well-known inhibitor of platelet aggregation, is extensively used for the prevention/treatment of coronary artery disease. The beneficial and antithrombotic effects of the compound are related to the inhibition of platelet cyclooxygenase. It is currently believed that aspirin has no effect on the formed thrombus, which results in coronary artery disease. It was found that the exposure of platelets to 4.0 lM aspirin either in vitro or in vivo resulted in fibrinolysis of the formed ''clot'' produced by the recalcification of platelet-rich plasma due to the production of NO in these cells by the compound. The lysis of clot in the presence of aspirin was found to be related to the fibrinolysis with simultaneous appearance of fibrin degradation products due to the generation of serine proteinase activity by NO in the assay mixture. The aspirin activated nitric oxide synthase that catalyzed the synthesis of NO in platelets was solubilized by Triton X-100 treatment and purified to homogeneity by chromatography on DEAE cellulose and Sephadex G-50 columns. The enzyme was found to be a single chain polypeptide with M.W. 19 kDa. The treatment of human plasminogen with NO was found to directly activate the zymogen to plasmin with the production of preactivation peptide in the absence of cofactors, or cells without the formation of cyclic GMP in the assay mixture. Am. J. Hematol. 82:986-995, 2007. V

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