Effects of P2Y1 and P2Y12 receptor antagonists on platelet aggregation induced by different agonists in human whole blood

ADP plays a major role in the amplification of platelet aggregation induced by other platelet agonists. ADP initiates platelet activation via the P2Y(1) receptor and amplifies platelet activation via the P2Y(12) receptor. Using the selective P2Y(1) receptor antagonist A2P5P and the selective P2Y(12) receptor antagonist AR-C69931MX, we assessed the relative contributions of P2Y(1) receptor and P2Y(12) receptor activation to platelet aggregation in hirudin-anticoagulated whole blood induced by PAF, 5HT, epinephrine, TRAP, streptokinase, U46619 and collagen. The effects of aspirin were assessed concurrently. A2P5P and AR-C69931MX variably inhibited aggregation induced by most of the agonists studied, whereas aspirin only inhibited aggregation induced by streptokinase and collagen. In some experiments, A2P5P and AR-C69931MX yielded additive inhibition of aggregation. All three antagonists interacted synergistically to inhibit collagen-induced aggregation. These studies demonstrate that P2Y(1) receptor activation plays a significant role in amplifying aggregation induced by agonists other than ADP, in addition to the established roles of P2Y(12) receptor activation and thromboxane A(2) synthesis.