Augmentation of U46619 induced human platelet aggregation by aspirin

Aspirin is known to suppress platelet function markedly. However, aspirin at concentrations higher than 1 mM was observed to augment 1.3 μM U46619 (a stable thromboxane receptor (TP receptor) agonist) induced human platelet aggregation in this study. Moreover, at a concentration as low as 250 μM aspirin increased the aggregation induced by U46619 in 13% of normal and healthy individuals. The degree of platelet aggregation and the amount of ATP release were enhanced in U46619 stimulated platelet rich plasma by the addition of aspirin (>250 μM). U46619 was previously reported to inhibit forskolin-stimulated adenyl cyclase and to reduce the cAMP formation. Both of the augmentation effects of aspirin on U46619-induced aggregation and ATP release were blocked by MeSAMP, a P2Y12 receptor antagonist. U46619 induced aggregation was suppressed by the addition of ADP scavenger (CP/CPK) with no significant change on ATP measured and the effect of CP/CPK could not be reversed by aspirin. In addition, aspirin augmented the inhibitory effect of U46619 on the cAMP production. Our present results suggested that the potentiation effect of aspirin on U46619 induced aggregation was related with the secreted ADP and the subsequent P2Y12/Gi related signaling.