Effect of OKY-046, a thromboxane A2 synthetase inhibitor, on arachidonate-induced platelet aggregation: possible role of "prostaglandin H2 steal" mechanism.
To clarify the mode of action of a selective thromboxane A2 (TXA2) blockade in platelet reactivity, we examined the effect of (E)-3-[4-(1-imidazolylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a potent TXA2 synthetase inhibitor, on human platelet aggregation induced by arachidonic acid (1 mM) in the absence and presence of aspirin-treated aortic microsomes containing prostacyclin (PGI2) synthetase activity ex vivo. The production of TXA2 and PGI2 in platelet rich plasma was determined by the amounts of their stable catabolites, TXB2 and 6-keto-PGF1 alpha respectively, measured by radioimmunoassay. In the absence of aortic microsomes, OKY-046 (greater than 10(-5) M) produced more than 90% inhibition of TXA2 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 PGI2 production, which paralleled the OKY-046-induced inhibition of TXA2. These results suggest that a selective TXA2 blockade produces effects on platelet aggregation mainly in dual fashion in the presence of PGI2 synthetase: one is due to mere inhibition of TXA2 synthetase and the other is due to the enhancement of PGI2 production probably involving "prostaglandin H2 (PGH2) steal" mechanism, in which PGH2 accumulated in platelets is partly converted to a substrate of PGI2 synthetase in aortic microsomes to produce PGI2.
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000648:ultrastructure; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D002417:Cattle; D006801:Humans; D066298:In Vitro Techniques; D008689:Methacrylates / Q000494:pharmacology*; D008861:Microsomes / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011449:Prostaglandin Endoperoxides / Q000502:physiology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000502:physiology*; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000502:physiology*
D000179:Acrylates; D001095:Arachidonic Acids; D008689:Methacrylates; D011449:Prostaglandin Endoperoxides; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D016718:Arachidonic Acid; D044262:Prostaglandin H2; C034364:ozagrel