EFFECT OF OKY-046, A THROMBOXANE A_2 SYNTHETASE INHIBITOR, ON ARACHIDONATE-INDUCED PLATELET AGGREGATION : POSSIBLE ROLE OF "PROSTAGLANDIN H_2 STEAL" MECHANISM

  • KUZUYA Tsunehiko
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • OHMORI Masaharu
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • HOSHIDA Shiro
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • YAMAGISHI Masakazu
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • INOUE Michitoshi
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • KAMADA Takenobu
    Division of Cardiology, First Department of Medicine, Osaka University School of Medicine
  • TADA Michihiko
    Department of Pathophysiology, Osaka University School of Medicine

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To clarify the mode of action of a selective thromboxane A_2 (TXA_2) blockade in platelet reactivity, we examined the effect of (E)-3-[4-(1-imidazolylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a potent TXA_2 synthetase inhibitor, on human platelet aggregation induced by arachidonic acid (1mM) in the absence and presence of aspirin-treated aortic microsomes containing prostacyclin (PGI_2) synthetase activity ex vivo. The production of TXA_2 and PGI_2 in platelet rich plasma was determined by the amounts of their stable catabolites, TXB_2 and 6-keto-PGF_<1α > respectively, measured by radioimmunoassay. In the absence of aortic microsomes, OKY-046 (>10^<-5> M) produced more than 90% inhibition of TXA_2 production, whereas platelet aggregation was less inhibited, about 40% inhibition, over control, by OKY-046 in that concentration. In the presence of aortic microsomes, the inhibitory effect of OKY-046 on platelet aggregation was markedly augmented in a dose-dependent manner in proportion to the increment of PGI_2 production, which paralleled the OKY-046-induced inhibition of TXA_2. These results suggest that a selective TXA_2 blockade produces effects on platelet aggregation mainly in dual fashion in the presence of PGI_2 synthetase : one is due to mere inhibition of TXA_2 synthetase and the other is due to the enhancement of PGI_2 production probably involving "prostaglandin H_2 (PGH_2) steal" mechanism, in which PGH_2 accumulated in platelets is partly converted to a substrate of PGI_2 synthetase in aortic microsomes to produce PGI_2.

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