Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo.
Vascular expression and cellular functions of the thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) suggest similar but distinct vascular regulatory roles. The vascular actions of PAR-1 and PAR-2 in vivo were differentiated by monitoring mean arterial pressure (MAP) and heart rate (HR) of anesthetized mice in response to intravenous SFLLRN (0.1, 0.3, and 1 mumol/kg) and SLIGRL (0.1, 0.3, and 1 mumol/kg), the respective receptor-activating sequences for PAR-1 and PAR-2, and TFLLRNPNDK (0.3, 1, and 3 mumol/kg), a synthetic peptide selective for PAR-1. All peptides dose dependently decreased MAP (order of potency: SLIGRL > SFLLRN > TFLLRNPNDK). SLIGRL induced a more prolonged hypotension with a slow return to baseline, whereas SFLLRN- and TFLLRNPNDK-induced hypotension was followed by a rapid return towards baseline 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 cumulative hypotensive response to SLIGRL but had no effect on the SFLLRN and TFLLRNPNDK hypotension. However, L-NAME revealed a rebound hypertension in response to SFLLRN and TFLLRNPNDK but not SLIGRL. In conclusion, activation of either PAR-1 or PAR-2 in vivo results in hypotension. In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction. Thus, these different hemodynamic responses in vivo suggest distinct physiological or pathophysiological roles for PAR-1 and PAR-2 in local vascular regulation.
Cheung
W M
WM
R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA. wcheungl@prius.jnj.com
Andrade-Gordon
P
P
Derian
C K
CK
Damiano
B P
BP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists*
D009842:Oligopeptides; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C082835:thrombin receptor peptide (42-47); D000109:Acetylcholine