Abstract
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 μM) induced relaxation of either 9,11-dideoxy-9α,11α-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 ofl-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 anl-NAME/ODQ/indomethacin-resistant relaxation of MA from PAR2 (+/+) mice. In contrast with SLI-NH2, tc-LI (>30 μM) 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, α1-adrenergic, neurokinin, thromboxane A2, histamine, angiotensin II, or endothelin-1 receptors failed to inhibit contractions by 50 μM tc-LI. At resting tension, SLI-NH2 (>10 μM) 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.
- The American Society for Pharmacology and Experimental Therapeutics
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