Abstract
The platelet P2Y1 ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y1 receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y1 receptor antagonist MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y1 receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y12 receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y1 receptor in thrombosis and validate the concept that targeting the P2Y1 receptor could be a relevant alternative or complement to current antiplatelet strategies.
Footnotes
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This work was supported by INSERM, Association de Recherche et Développment en Médecine et Santé Publique, Etablissement Français du Sang-Alsace, and Fondation de France (2002005149).
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doi:10.1124/jpet.105.094037.
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ABBREVIATIONS: P2X1 and P2Y1, platelet P2X1 and platelet P2Y1, respectively; WT, wild type; PRP, platelet-rich plasma; U46619, 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α; DIOC6, 3,3′-dihexyloxacarbocyanine iodide; MRS2179, 2′-deoxy-N6-methyl adenosine 3′,5′-diphosphate; MRS2500, 2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate; NF449, 4,4′,4″,4′″-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino))) tetrakis-benzene-1,3-disulfonic acid octasodium salt; A3P5P, adenosine-3′-phosphate-5′-phosphate.
- Received August 9, 2005.
- Accepted October 17, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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