14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP(2) 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 (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.
Yang
Cui
C
Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.
Kwan
Yiu-Wa
YW
Au
Alice Lai-Shan
AL
Poon
Christina Chui-Wa
CC
Zhang
Qian
Q
Chan
Shun-Wan
SW
Lee
Simon Ming-Yuen
SM
Leung
George Pak-Heng
GP
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*
D058307:Receptors, Prostaglandin E, EP2 Subtype; D014665:Vasodilator Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid