Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin.
BACKGROUND
Activation of two receptors for adenosine diphosphate (ADP), P2Y(1) and P2Y(12), is necessary for ADP-induced platelet aggregation (PA). It is generally believed that the antithrombotic effects of drugs inhibiting P2Y(12), such as clopidogrel, are uniquely mediated by inhibition of P2Y(12)-dependent PA. However, as P2Y(12) is negatively coupled to adenylyl cyclase (AC), its inhibition may also exert antithrombotic effects through the potentiation of prostacyclin (PGI(2)), which inhibit PA by stimulating AC.


OBJECTIVE
To test whether inhibition of P2Y(12) potentiates the antiplatelet effects of PGI(2).


METHODS
We measured the effects of PGI(2) (0.01-10 microm) on PA of washed human platelets induced by thrombin (0.5 U mL(-1)) in the presence or absence of ARC69931MX (anti-P2Y(12)) or MRS2500 (anti-P2Y(1)).


RESULTS
PGI(2) inhibited PA in the presence of anti-P2Y(12), but not in the presence of anti-P2Y(1) or in the absence of inhibitors. In contrast, dibutyryl-cyclicAMP inhibited PA both in the presence and absence of anti-P2Y(1) or anti-P2Y(12). PGI(2) increased platelet cyclicAMP levels only in the absence of thrombin or in the presence of thrombin plus anti-P2Y(12).


CONCLUSIONS
PGI(2) did not inhibit PA induced by thrombin, because its effect on AC was prevented by released ADP interacting with P2Y(12). Anti-P2Y(12) drugs, by rescuing AC activity, potentiate the antiplatelet effect of PGI(2), which may contribute to their antithrombotic effect.
Cattaneo
M
M
Unità di Ematologia e Trombosi, Ospedale San Paolo, Dipartimento di Medicina, Chirurgia e Odontoiatria, Università di Milano, Milan, Italy. cattaneo@unimi.it
Lecchi
A
A
D000244:Adenosine Diphosphate / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003563:Cyclic CMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D011464:Epoprostenol / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D012701:Serotonin; D003563:Cyclic CMP; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C053441:dibutyryl cyclic-3',5'-cytidine monophosphate; C117446:cangrelor; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D000262:Adenylyl Cyclases