Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2)and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2or PAR-1

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 H R decreases at 1 mu mol/kg. TFLLRNPNDK also caused secondary hypertension f ollowing L-NAME pretreatment. These responses were absent in PAR-1(-/-) mic e. In WT mice, SLIGRL, a PAR-2 selective activating peptide, caused hypoten sion without changing HR at 0.3 mu mol/kg. SLIGRL did not induce hypertensi on following N omega-nitro-L-arginine-methyl ester-HCl (L-NAME). The respon se 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 m u mol/kg, as well as secondary hypertension following L-NAME. SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hyper tension following L-NAME were absent. The hypotensive and bradycardic respo nses to SFLLRN and TFLLRNPNDK in PAR-2-/- mice were accentuated compared wi th WT mice. By using mouse strains deficient in either PAR-1 or PAR-2, we c onfirmed the in vivo specificity of TFLLRNPNDK and SLIGRL as respective act ivating peptides for PAR-1 and PAR-2, and the distinct hemodynamic response s mediated by activation of PAR-1 or PAR-2. Moreover, the accentuated respo nse to PAR-1 activation in PAR-2-deficient mice suggests a compensatory res ponse and potential receptor cross-talk.