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Vol. 298, Issue 1, 34-42, July 2001
Drug Discovery, The R. W. Johnson Pharmaceutical Research
Institute, Spring House, Pennsylvania
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.
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