TY - JOUR T1 - Administration of a Potent Antagonist of Protease-Activated Receptor-1 (PAR-1) Attenuates Vascular Restenosis Following Balloon Angioplasty in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 34 LP - 42 VL - 298 IS - 1 AU - Patricia Andrade-Gordon AU - Claudia K. Derian AU - Bruce E. Maryanoff AU - Han-Cheng Zhang AU - Michael F. Addo AU - Wai-man Cheung AU - Bruce P. Damiano AU - Michael R. D'Andrea AU - Andrew L. Darrow AU - Lawrence de Garavilla AU - Annette J. Eckardt AU - Edward C. Giardino AU - Barbara J. Haertlein AU - David F. McComsey Y1 - 2001/07/01 UR - http://jpet.aspetjournals.org/content/298/1/34.abstract N2 - Human platelets possess two distinct thrombin-activated receptors, PAR-1 (protease-activated receptor-1) and PAR-4, whereas human vascular smooth muscle cells possess only PAR-1. Although such thrombin receptors have been studied extensively in vitro, their physiological roles are still rather ill-defined. We have now employed a potent, selective PAR-1 antagonist, RWJ-58259, to probe the in vivo significance of PAR-1 in thrombosis and vascular injury. RWJ-58259 was examined in two thrombosis models in guinea pigs: the arteriovenous (A-V) shunt assay (monitoring thrombus weight) and the Rose Bengal intravascular photoactivation assay (monitoring time to occlusion). Administration of RWJ-58259 (10 mg/kg, total i.v. dose) did not inhibit thrombus formation in either thrombosis model, although local, intrashunt delivery in the A-V shunt model did elicit a modest antithrombotic effect (thrombus weight reduction from 35 ± 2 to 24 ± 4 mg). These results are consistent with the presence of more than one thrombin-sensitive receptor on guinea pig platelets, in analogy with human platelets. Indeed, we were able to establish that guinea pig platelets express three thrombin receptors, PAR-1, PAR-3, and PAR-4. We also examined RWJ-58259 in a vascular restenosis model involving balloon angioplasty in rats. Perivascular administration of RWJ-58259 (10 mg) significantly reduced neointimal thickness (77 ± 5 μm to 45 ± 5 μm, P < 0.05), clearly demonstrating an important role for PAR-1 in vascular injury. From these results, it is evident that a PAR-1 antagonist is not especially effective for treating platelet-dependent thrombosis; however, it could well be beneficial for treating restenosis attendant to arterial injury. The American Society for Pharmacology and Experimental Therapeutics ER -