In vivo and in vitro effects of nafazatrom (Bay g 6575), an antithrombotic compound, on arachidonic acid metabolism in platelets and vascular tissue

Abstract

Nafazatrom, given acutely to male volunteers, had no effect on platelet aggregation, associated thromboxane B2 (TXB2) formation or the evaluated hormonal, renal and cardiovascular parameters. Only slight increases in plasma levels of 6-keto-PGF1 alpha and in platelet counts were observed. However, a marked influence of nafazatrom on arachidonic acid metabolism in certain in vitro systems was found. Prostaglandin synthesis by rabbit kidney cortex microsomes was significantly enhanced, PGI2 being stimulated the most. In normal human platelets arachidonic acid metabolism was not influenced significantly by nafazatrom which was taken up by the platelets in a dose-dependent manner. In contrast, in platelets with a high peroxide level probably due to depletion of reducing cofactors, 12-hydroperoxy-eicosatetraenoic acid was transformed to 12-hydroxy-eicosatetetraenoic acid by nafazatrom, while the formation of TXB2 was stimulated. These findings suggest that nafazatrom may act as a reducing cofactor for the hydroperoxidase involved in the cyclooxygenase- and lipoxygenase-pathways of arachidonic acid metabolism.