title: Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide.
abstract: Circulating platelets are constantly exposed to nitric oxide (NO) released from the vascular endothelium. This NO acts to reduce platelet reactivity, and in so doing blunts platelet aggregation and thrombus formation. For successful hemostasis, platelet activation and aggregation must occur at sites of vascular injury despite the constant presence of NO. As platelets aggregate, they release secondary mediators that drive further aggregation. Particularly significant among these secondary mediators is ADP, which, acting through platelet P2Y12 receptors, strongly amplifies aggregation. Platelet P2Y12 receptors are the targets of very widely used antithrombotic drugs such as clopidogrel, prasugrel, and ticagrelor. Here we show that blockade of platelet P2Y12 receptors dramatically enhances the antiplatelet potency of NO, causing a 1,000- to 100,000-fold increase in inhibitory activity against platelet aggregation and release reactions in response to activation of receptors for either thrombin or collagen. This powerful synergism is explained by blockade of a P2Y12 receptor-dependent, NO/cGMP-insensitive phosphatidylinositol 3-kinase pathway of platelet activation. These studies demonstrate that activation of the platelet ADP receptor, P2Y12, severely blunts the inhibitory effects of NO. The powerful antithrombotic effects of P2Y12 receptor blockers may, in part, be mediated by profound potentiation of the effects of endogenous NO.
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Martina H
authors.initials: MH
authors.lastname: Lundberg
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.forename: Ivana
authors.initials: I
authors.lastname: Vojnovic
authors.forename: Antonia B
authors.initials: AB
authors.lastname: Solomon
authors.forename: Michael
authors.initials: M
authors.lastname: Emerson
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002097:C-Reactive Protein / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D009569:Nitric Oxide / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002097:C-Reactive Protein; D011464:Epoprostenol; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D013917:Thrombin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020827:rap1 GTP-Binding Proteins; D006152:Cyclic GMP; D002118:Calcium
keywords: anti-platelet therapy; atherothrombosis; prostacyclin