Inhibition of ADP-induced intracellular Ca2+ responses and platelet aggregation by the P2Y12 receptor antagonists AR-C69931MX and clopidogrel is enhanced by prostaglandin E1.
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.
Fox
S C
SC
Cardiovascular Medicine, University Hospital, Queen's Medical Centre, University of Nottingham, Nottingham, UK. sue.fox@nottingham.ac.uk
Behan
M W H
MW
Heptinstall
S
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D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000527:Alprostadil / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D000077144:Clopidogrel; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors
D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D000077144:Clopidogrel; D000527:Alprostadil; D013988:Ticlopidine; D002118:Calcium