Inhibition of ADP-induced intracellular Ca 2+ responses and platelet aggregation by the P2Y 12 receptor antagonists AR-C69931MX and clopidogrel is enhanced by prostaglandin E 1

Abstract

P2Y 12 antagonists such as clopidogrel and AR-C69931MX inhibit aggregation by antagonizing the effects of ADP at P2Y 12 receptors on platelets. Agents such as PGE 1 also inhibit aggregation by stimulating adenylate cyclase to produce cAMP, which interferes with Ca 2+ mobilization within the cell. Since one facet of P2Y 12 receptors is that they mediate inhibition of adenylate cyclase by ADP, it might be expected that P2Y 12 antagonists would interact with PGE 1. We have explored the effects of PGE 1 and AR-C69931MX singly and in combination on ADP-induced intracellular Ca 2+ ([Ca 2+] i) responses and aggregation. PGE 1 alone caused parallel dose-dependent inhibition of [Ca 2+] i and aggregation responses. AR-C66931MX alone caused only partial inhibition of [Ca 2+] i despite a marked inhibitory effect on aggregation. Combinations of PGE 1 with AR-C66931MX were found to act in synergy to reduce both [Ca 2+] i and aggregation. This effect was confirmed in patients with acute coronary syndromes by studying the inhibitory effects of PGE 1 on [Ca 2+] i and aggregation before and after clopidogrel. In summary, we have shown that P2Y 12 antagonists interact with natural agents such as PGE 1 to provide more effective inhibition of [Ca 2+] i and platelet aggregation. This would contribute to the effectiveness of P2Y 12 antagonists as antithrombotic agents in man.