RECEPTOR-ACTIVATING PEPTIDES DISTINGUISH THROMBIN RECEPTOR (PAR-1) AND PROTEASE ACTIVATED RECEPTOR-2 (PAR-2) MEDIATED HEMODYNAMIC-RESPONSESIN-VIVO

Vascular expression and cellular functions of the thrombin receptor (P AR-1) and protease activated receptor 2 (PAR-2) suggest similar but di stinct vascular regulatory roles. The vascular actions of PAR-I and PA R-2 in vivo were differentiated by monitoring mean arterial pressure ( MAP) and heart rate (HR) of anesthetized mice in response to intraveno us SFLLRN (0.1, 0.3, and 1 mu mol/kg) and SLIGRL (0.1, 0.3, and 1 mu m ol/kg), the respective receptor-activating sequences for PAR-1 and PAR -2, and TFLLRNPNDK (0.3, 1, and 3 mu mol/kg), a synthetic peptide sele ctive for PAR-1. All peptides dose dependently decreased MAP (order of potency: SLIGRL > SFLLRN > TFLLRNPNDK). SLIGRL induced a more prolong ed hypotension with a slow return to baseline, whereas SFLLRN- and TFL LRNPNDK-induced hypotension was followed by a rapid return towards bas eline and a sustained moderate hypotension SFLLRN and TFLLRNPNDK, but not SLIGRL, decreased HR. N-omega-Nitro-L-arginine methyl ester HCl (L -NAME), an inhibitor of nitric oxide synthesis, attenuated the cumulat ive hypotensive response to SLIGRL but had no effect on the SFLLRN and TFLLRNPNDK hypotension. However, L-NAME revealed a rebound hypertensi on in response to SFLLRN and TFLLRNPNDK but not SLIGRL. In conclusion, activation of either PAR-I or PAR-2 in vivo results In hypotension. I n addition, only PAR-1 activation induced hypertension following L-NAM E, reflecting concurrent PAR-1-mediated vasoconstriction. Thus, these different hemodynamic responses in vivo suggest distinct physiological or pathophysiological roles for PAR-I and PAR-2 in local vascular reg ulation.