14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP2 receptors in rat mesenteric artery

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 (EP2 receptor antagonist), whereas SC19220 (EP1 receptor antagonist), L798106 (EP3 receptor antagonist) and GW627368X (EP4 receptor antagonist) had no effect The effect of 14,15-EET and the mechanism involved was mimicked by prostaglandin E-2 (an EP2 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 EP2 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 EP2 receptors This subsequently leads to activation of cAMP/PKA-dependent pathway in vascular smooth muscle cells (C) 2010 Elsevier Inc All rights reserved.