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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