Formation of PGD2Contributes to the Anti-aggregatory Efficacy of ZD1542, a Thromboxane A2Synthase Inhibitor and TP Receptor Antagonist, in Human Whole Blood

Abstract

The aim of this study was to determine the contribution of increased PGD(2) formation to the anti-aggregatory action of a thromboxane A(2) (TXA(2)) synthase inhibitor and TP receptor antagonist (ZD1542) against collagen-induced human platelet aggregation in citrated whole blood using the prostaglandin (PG) DP receptor antagonists AH6809 and 868C84. ZD1542 (1 μM) was markedly more effective than aspirin (1 mM) against collagen-induced aggregation (73 vs 52% inhibition respectively), and formation of both PGI(2) and PGD(2) was evident in the presence of ZD1542. Added PGD(2) (30 nM) inhibited aggregation to a similar extent as did ZD1542 (68% inhibition) and the antiaggregatory action of PGD(2) was abolished, both by AH6809 (50 μM) and by 868C84 (0.5 μM). AH6809 significantly reduced the antiaggregatory efficacy of ZD1542, but did not modify the efficacy of aspirin. In contrast, 868C84 had little effect on the antiaggregatory efficacy of ZD1542 whereas 868C84 in combination with aspirin inhibited platelet aggregation more markedly than did aspirin alone. These findings indicate that formation of PGD(2) contributes to the antiaggregatory action of ZD1542 against collagen-induced human platelet aggregation. However, results obtained with the DP receptor antagonist 868C84 were inconclusive since 868C84 has a limited inhibitory effect against collagen-induced human platelet aggregation which is independent of eicosanoid formation.