Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Background: Activation of two receptors for adenosine diphosphate (ADP), P2Y1 and P2Y12, is necessary for ADP-induced platelet aggregation (PA). It is generally believed that the antithrombotic effects of drugs inhibiting P2Y12, such as clopidogrel, are uniquely mediated by inhibition of P2Y12 -dependent PA. However, as P2Y12 is negatively coupled to adenylyl cyclase (AC), its inhibition may also exert antithrombotic effects through the potentiation of prostacyclin (PGI2), which inhibit PA by stimulating AC. Objectives: To test whether inhibition of P2Y12 potentiates the antiplatelet effects of PGI2. Methods: We measured the effects of PGI2 (0.01-10 μ m) on PA of washed human platelets induced by thrombin (0.5 U mL-1) in the presence or absence of ARC69931MX (anti-P2Y2) or MRS2500 (anti-P2Y1). Results: PGI2 inhibited PA in the presence of anti-P2Y12, but not in the presence of anti-P2Y1 or in the absence of inhibitors. In contrast, dibutyryl-cyclicAMP inhibited PA both in the presence and absence of anti-P2Y1 or anti-P2Y12. PGI2 increased platelet cyclicAMP levels only in the absence of thrombin or in the presence of thrombin plus anti-P2Y12. Conclusions: PGI2 did not inhibit PA induced by thrombin, because its effect on AC was prevented by released ADP interacting with P2Y12. Anti-P2Y12 drugs, by rescuing AC activity, potentiate the antiplatelet effect of PGI2, which may contribute to their antithrombotic effect.