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
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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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