Proteinase-activated receptor-2 (PAR2): Vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2

John J. McGuire, Jiazhen Dai, Patricia Andrade-Gordon, Christopher Triggle, Morley D. Hollenberg

Research output: Contribution to journalArticle

38 Citations (Scopus)

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-Leulle-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 endotheliumintact 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-NG-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 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.

Original languageEnglish
Pages (from-to)985-992
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number3
DOIs
Publication statusPublished - 1 Dec 2002
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Pharmacology

Cite this