RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 671
OP 678
VO 288
IS 2
A1 Bruce P. Damiano
A1 Wai-Man Cheung
A1 Rosemary J. Santulli
A1 Wai-Ping Fung-Leung
A1 Karen Ngo
A1 Richard D. Ye
A1 Andrew L. Darrow
A1 Claudia K. Derian
A1 Lawrence de Garavilla
A1 Patricia Andrade-Gordon
YR 1999
UL http://jpet.aspetjournals.org/content/288/2/671.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics