title: An omega-3 epoxide of docosahexaenoic acid lowers blood pressure in angiotensin-II-dependent hypertension.
abstract: Mediators of antihypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxy docosapentaenoic acid), is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and antihypertensive arachidonic acid epoxides, epoxyeicosatrienoic acids (EETs). Based in part on plasma levels of EDPs after a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the antihypertensive actions of DHA in angiotensin-II (Ang-II)-dependent hypertension. Treatment individually with 19, 20-EDP and a potent sEH inhibitor TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared with Ang-II-infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected not only most metabolites of the P450 pathway but also renal levels of prostaglandin-E2. Our findings suggest that 19, 20-EDP is a mediator of the antihypertensive effects of DHA in Ang-II-dependent hypertension. It seems that 19, 20-EDP requires metabolic stabilization with a sEH inhibitor to be most effective in lowering BP, although both TPPU and 19, 20-EDP are so effective on their own that demonstrating additive or synergistic interactions is difficult.
authors.affiliation: *Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA; and †School of Veterinary Medicine, Anatomy, Physiology and Cell Biology, University of California, Davis, CA.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.forename: Kin Sing
authors.initials: KS
authors.lastname: Stephen Lee
authors.forename: Christina
authors.initials: C
authors.lastname: Miyabe
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Hammock
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D000959:Antihypertensive Agents; D015525:Fatty Acids, Omega-3; D010671:Phenylurea Compounds; D010880:Piperidines; D000804:Angiotensin II; D004281:Docosahexaenoic Acids; D004851:Epoxide Hydrolases