title: Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes, obesity and hypertension.
abstract: Endothelial dysfunction is a hallmark of, and plays a pivotal role in the pathogenesis of cardiometabolic diseases, including type II diabetes, obesity, and hypertension. It has been well established that epoxyeicosatrienoic acids (EETs) act as an endothelial derived hyperpolarization factor (EDHF). Soluble epoxide hydrolase (s-EH) rapidly hydrolyses certain epoxylipids (e.g. EETs) to less bioactive diols (DHETs), thereby attenuating the evoked vasodilator effects. The aim of the present study was to examine if inhibition of s-EH can restore impaired endothelial function in three animal models of cardiometabolic diseases. Isolated vessel rings of the aorta and/or mesenteric artery from mice or rats were pre-contracted using phenylephrine or U46619. Endothelium-dependent and independent vasorelaxation to acetylcholine and sodium nitroprusside (SNP) were measured using wire myography in vessels isolated from db/db or diet-induced obesity (DIO) mice, and angiotensin II-induced hypertensive rats treated chronically with s-EH inhibitors AR9281 or AR9276 or with vehicle. Vasorelaxation to acetylcholine, but not to SNP was severely impaired in all three animal models. Oral administration of AR9281 or AR9276 abolished whole blood s-EH activity, elevated epoxy/diol lipid ratio, and abrogated endothelial dysfunction in all three models. Incubating the mesenteric artery of db/db mice with L-NAME and indomethacin to block nitric oxide (NO) and prostacyclin formation did not affect AR9821-induced improvement of endothelial function. These data indicate that inhibition of s-EH ameliorates endothelial dysfunction and that effects in the db/db model are independent of the presence of NO and cyclooxygenase derived prostanoids. Thus, preserving vasodilator EETs by inhibition of s-EH may be of therapeutic benefit by improving endothelial function in cardiometabolic diseases.
authors.affiliation: Arete Therapeutics Inc., South San Francisco, CA 94080, USA.
authors.forename: Le-Ning
authors.initials: LN
authors.lastname: Zhang
authors.forename: Jon
authors.initials: J
authors.lastname: Vincelette
authors.forename: Dawn
authors.initials: D
authors.lastname: Chen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gless
authors.forename: Sampath-Kumar
authors.initials: SK
authors.lastname: Anandan
authors.forename: Gabor M
authors.initials: GM
authors.lastname: Rubanyi
authors.forename: Heather K
authors.initials: HK
authors.lastname: Webb
authors.forename: D Euan
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: Yi-Xin Jim
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C557705:1-(1-acetyl-piperidine-4-yl)-3-adamantan-1-yl-urea; C557706:1-(1-nicotinoylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea; D010671:Phenylurea Compounds; D009536:Niacinamide; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane