title: Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats.
abstract: Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.
authors.affiliation: Department of Biological Sciences, Federal University of Goias, Jatai, GO, Brazil.
authors.forename: Nubia S
authors.initials: NS
authors.lastname: Lobato
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Filgueira
authors.forename: Roshini
authors.initials: R
authors.lastname: Prakash
authors.forename: Fernanda R
authors.initials: FR
authors.lastname: Giachini
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C078814:anandamide