title: 14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP(2) receptors in rat mesenteric artery.
abstract: Epoxyeicosatrienoic acids (EETs) induce vasorelaxation, probably through G protein-coupled receptors. The identity of these receptors is unclear, but it has been reported that EETs may bind to peroxisome proliferator activated receptors (PPARs) and E-prostanoid (EP) receptors. Therefore, we studied whether PPARs or EP receptors were involved in 14,15-EET-induced vasorelaxation. Isometric tensions of rat mesenteric arteries were measured. The vasorelaxant effect of 14,15-EET was inhibited by NF449 (G(s)-protein inhibitor), Rp-cAMP (cAMP antagonist) and KT5720 (PKA inhibitor), suggesting that the effect of 14,15-EET was mediated through G(s) protein-coupled receptors which were linked to the cAMP/PKA-dependent pathway. Pretreatments with MK886 (PPAR(alpha) antagonist) and GW9662 (PPAR(gamma) antagonist) did not influence 14,15-EET-induced vasorelaxation. The vasorelaxant effect of 14,15-EET was inhibited by AH6809 (EP(2) receptor antagonist), whereas SC19220 (EP(1) receptor antagonist), L798106 (EP(3) receptor antagonist) and GW627368X (EP(4) receptor antagonist) had no effect. The effect of 14,15-EET and the mechanism involved was mimicked by prostaglandin E(2) (an EP(2) receptor agonist). The 14,15-EET-induced relaxation was slightly potentiated in the presence of indomethacin (cyclooxygenase inhibitor which block PGE(2) synthesis). Binding study showed that the amount of 14,15-EET bound to the cell membrane of rat mesenteric arterial smooth muscle cells was much higher than that bound to the nuclear membrane. The binding of 14,15-EET to the cell membrane was attenuated by AH6809 and siRNA against EP(2) receptors. In conclusion, our study has demonstrated that 14,15-EET exerts relaxant effects on rat mesenteric arteries, at least partly via the stimulation of EP(2) receptors. This subsequently leads to activation of cAMP/PKA-dependent pathway in vascular smooth muscle cells.
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.
authors.forename: Cui
authors.initials: C
authors.lastname: Yang
authors.forename: Yiu-Wa
authors.initials: YW
authors.lastname: Kwan
authors.forename: Alice Lai-Shan
authors.initials: AL
authors.lastname: Au
authors.forename: Christina Chui-Wa
authors.initials: CC
authors.lastname: Poon
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Shun-Wan
authors.initials: SW
authors.lastname: Chan
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.forename: George Pak-Heng
authors.initials: GP
authors.lastname: Leung
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058307:Receptors, Prostaglandin E, EP2 Subtype; D014665:Vasodilator Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid