title: Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats.
abstract: Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (V(max)) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg(-1)·day(-1) for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg (P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml (P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15-trans-EET was more potent (ED(50) 10(-10) M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED(50) 10(-9) M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and trans-isomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.
authors.affiliation: Dept. of Pharmacology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA. houli_jiang@nymc.edu
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.forename: John
authors.initials: J
authors.lastname: Quilley
authors.forename: Anabel B
authors.initials: AB
authors.lastname: Doumad
authors.forename: Angela G
authors.initials: AG
authors.lastname: Zhu
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Charles T
authors.initials: CT
authors.lastname: Stier
authors.forename: Mairead A
authors.initials: MA
authors.lastname: Carroll
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood; D000818:Animals; D001095:Arachidonic Acids / Q000097:blood*; D019817:Benzoic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000097:blood* / Q000503:physiopathology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D001095:Arachidonic Acids; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; D019817:Benzoic Acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid