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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCARDIOVASCULAR

Administration of a Potent Antagonist of Protease-Activated Receptor-1 (PAR-1) Attenuates Vascular Restenosis Following Balloon Angioplasty in Rats

Patricia Andrade-Gordon, Claudia K. Derian, Bruce E. Maryanoff, Han-Cheng Zhang, Michael F. Addo, Wai-man Cheung, Bruce P. Damiano, Michael R. D'Andrea, Andrew L. Darrow, Lawrence de Garavilla, Annette J. Eckardt, Edward C. Giardino, Barbara J. Haertlein and David F. McComsey
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 34-42;
Patricia Andrade-Gordon
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Claudia K. Derian
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Bruce E. Maryanoff
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Han-Cheng Zhang
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Michael F. Addo
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Wai-man Cheung
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Bruce P. Damiano
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Michael R. D'Andrea
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Andrew L. Darrow
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Lawrence de Garavilla
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Annette J. Eckardt
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Edward C. Giardino
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Barbara J. Haertlein
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David F. McComsey
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Abstract

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.

Footnotes

  • ↵1  A. Darrow, C. Derian, M. Addo, and P. Andrade-Gordon, manuscript in preparation.

  • Abbreviations:
    PAR
    protease-activated receptor
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    bp
    base pairs
    • Received December 26, 2000.
    • Accepted March 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCARDIOVASCULAR

Administration of a Potent Antagonist of Protease-Activated Receptor-1 (PAR-1) Attenuates Vascular Restenosis Following Balloon Angioplasty in Rats

Patricia Andrade-Gordon, Claudia K. Derian, Bruce E. Maryanoff, Han-Cheng Zhang, Michael F. Addo, Wai-man Cheung, Bruce P. Damiano, Michael R. D'Andrea, Andrew L. Darrow, Lawrence de Garavilla, Annette J. Eckardt, Edward C. Giardino, Barbara J. Haertlein and David F. McComsey
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 34-42;

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Research ArticleCARDIOVASCULAR

Administration of a Potent Antagonist of Protease-Activated Receptor-1 (PAR-1) Attenuates Vascular Restenosis Following Balloon Angioplasty in Rats

Patricia Andrade-Gordon, Claudia K. Derian, Bruce E. Maryanoff, Han-Cheng Zhang, Michael F. Addo, Wai-man Cheung, Bruce P. Damiano, Michael R. D'Andrea, Andrew L. Darrow, Lawrence de Garavilla, Annette J. Eckardt, Edward C. Giardino, Barbara J. Haertlein and David F. McComsey
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 34-42;
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