Proteinase-activated receptor-2 (PAR2): vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2.
We studied the actions of the proteinase-activated receptor-2-activating peptide (PAR2-AP) trans-cinnamoyl-LIGRLO-amide (tc-LI) in femoral (FA), renal, and small mesenteric (MA) arterial vessels from C57BL/6 [PAR2 (+/+)] and PAR2 (-/-) mice. The actions of tc-LI were compared with those of the parent PAR2-AP Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-amide; SLI-NH2). Either SLI-NH2 or tc-LI (0.1-10 microM) induced relaxation of either 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619)- or cirazoline-precontracted FA from PAR2 (+/+) in endothelium-intact preparations but did not relax vessels from PAR2 (-/-) mice. This FA relaxation by SLI-NH2 and by tc-LI was inhibited by 1) pretreatment with a combination of L-N(G)-nitroarginine methyl ester (L-NAME) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 2) precontraction with 30 mM KCl, or 3) removal of the endothelium. In contrast, tc-LI caused an L-NAME/ODQ/indomethacin-resistant relaxation of MA from PAR2 (+/+) mice. In contrast with SLI-NH2, tc-LI (>30 microM) contracted arteries from both PAR2 (-/-) and PAR2 (+/+) mice. Pretreatment of tissues with a combination of cyclopiazonic acid plus caffeine reduced significantly tc-LI-induced contractions, whereas nifedipine, CdCl2, and Ca2+-free conditions did not. Inhibitors of vascular muscarinic, alpha1-adrenergic, neurokinin, thromboxane A2, histamine, angiotensin II, or endothelin-1 receptors failed to inhibit contractions by 50 microM tc-LI. At resting tension, SLI-NH2 (>10 microM) contracted all arteries in an endothelium-independent manner but only from PAR2 (+/+) mice. We conclude that the endothelium-dependent vasodilation initiated by SLI-NH2 and tc-LI, but not the endothelium-independent contraction initiated by tc-LI, are due to the activation of PAR2. Indeed, the data from PAR2 (-/-) mice indicate that tc-LI, in addition to activating PAR2, is an agonist of vascular smooth muscle contraction via a receptor different than PAR2.
McGuire
John J
JJ
Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. mcguire@ucalgary.ca
Dai
Jiazhen
J
Andrade-Gordon
Patricia
P
Triggle
Chris R
CR
Hollenberg
Morley D
MD
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology* / Q000502:physiology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists* / Q000172:deficiency* / Q000235:genetics; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D009842:Oligopeptides; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C113425:cinnamoyl-LIGRLO-amide