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Research ArticleArticle

Cardiovascular Responses Mediated by Protease-Activated Receptor-2 (PAR-2) and Thrombin Receptor (PAR-1) are Distinguished in Mice Deficient in PAR-2 or PAR-1

Bruce P. Damiano, Wai-Man Cheung, Rosemary J. Santulli, Wai-Ping Fung-Leung, Karen Ngo, Richard D. Ye, Andrew L. Darrow, Claudia K. Derian, Lawrence de Garavilla and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 671-678;
Bruce P. Damiano
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Wai-Man Cheung
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Rosemary J. Santulli
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Wai-Ping Fung-Leung
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Karen Ngo
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Richard D. Ye
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Andrew L. Darrow
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Claudia K. Derian
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Lawrence de Garavilla
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Patricia Andrade-Gordon
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Abstract

We developed mice deficient in protease-activated receptor-2 (PAR-2) or PAR-1 to explore the pathophysiological functions of these receptors. In this report, we evaluated mean arterial pressure and heart rate (HR) changes in response to PAR-1 or PAR-2 activation in anesthetized wild-type (WT), PAR-1-deficient (PAR-1-/-), and PAR-2-deficient (PAR-2-/-) mice. In WT mice, TFLLRNPNDK, a PAR-1 selective activating peptide, caused hypotension and HR decreases at 1 μmol/kg. TFLLRNPNDK also caused secondary hypertension followingl-NAME pretreatment. These responses were absent in PAR-1−/− mice. In WT mice, SLIGRL, a PAR-2 selective activating peptide, caused hypotension without changing HR at 0.3 μmol/kg. SLIGRL did not induce hypertension followingNω-nitrol-arginine-methyl ester-HCl (l-NAME). The response to SLIGRL was absent in PAR-2-/- mice. SFLLRN, a nonselective receptor activating peptide caused hypotension and HR decreases in WT mice at 0.3 μmol/kg, as well as secondary hypertension followingl-NAME. SFLLRN still induced hypotension in PAR-1−/− mice, but HR decrease and secondary hypertension following l-NAME were absent. The hypotensive and bradycardic responses to SFLLRN and TFLLRNPNDK in PAR-2−/− mice were accentuated compared with WT mice. By using mouse strains deficient in either PAR-1 or PAR-2, we confirmed the in vivo specificity of TFLLRNPNDK and SLIGRL as respective activating peptides for PAR-1 and PAR-2, and the distinct hemodynamic responses mediated by activation of PAR-1 or PAR-2. Moreover, the accentuated response to PAR-1 activation in PAR-2-deficient mice suggests a compensatory response and potential receptor cross-talk.

Footnotes

  • Send reprint requests to: Bruce P. Damiano, Drug Discovery, R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477. E-mail: bdamiano{at}prius.jnj.com

  • Abbreviations:
    PAR-1
    protease-activated receptor-1
    PAR-2 protease-activated receptor-2
    MAP, mean arterial pressure
    HR
    heart rate
    L-NAME
    Nω-nitro-l-arginine-methyl ester-HCl
    • Received May 22, 1998.
    • Accepted September 11, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Cardiovascular Responses Mediated by Protease-Activated Receptor-2 (PAR-2) and Thrombin Receptor (PAR-1) are Distinguished in Mice Deficient in PAR-2 or PAR-1

Bruce P. Damiano, Wai-Man Cheung, Rosemary J. Santulli, Wai-Ping Fung-Leung, Karen Ngo, Richard D. Ye, Andrew L. Darrow, Claudia K. Derian, Lawrence de Garavilla and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 671-678;

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Research ArticleArticle

Cardiovascular Responses Mediated by Protease-Activated Receptor-2 (PAR-2) and Thrombin Receptor (PAR-1) are Distinguished in Mice Deficient in PAR-2 or PAR-1

Bruce P. Damiano, Wai-Man Cheung, Rosemary J. Santulli, Wai-Ping Fung-Leung, Karen Ngo, Richard D. Ye, Andrew L. Darrow, Claudia K. Derian, Lawrence de Garavilla and Patricia Andrade-Gordon
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 671-678;
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