Mode of action of P2Y₁₂ antagonists as inhibitors of platelet function

 

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Summary

P2Y₁₂ receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y₁₂ receptors. However, some P2Y₁₂ receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y₁₂ antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y₁₂ receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A_2A agonists, which act at G_s-coupled receptors. All three P2Y₁₂ antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A₂ mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y₁₂ antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the G_s-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y₁₂ antagonists acting through PAR1, TP, IP, EP4, A_2A or EP3 receptors. All three P2Y₁₂ antagonists enhanced VASPphosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A_2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y₁₂ receptors and not through another G-protein-coupled receptor.

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