title: Endothelial dysfunction in DOCA-salt-hypertensive mice: role of neuronal nitric oxide synthase-derived hydrogen peroxide.
abstract: Endothelial dysfunction is a common problem associated with hypertension and is considered a precursor to the development of micro- and macro-vascular complications. The present study investigated the involvement of nNOS (neuronal nitric oxide synthase) and H2O2 (hydrogen peroxide) in the impaired endothelium-dependent vasodilation of the mesenteric arteries of DOCA (deoxycorticosterone acetate)-salt-hypertensive mice. Myograph studies were used to investigate the endothelium-dependent vasodilator effect of ACh (acetylcholine). The expression and phosphorylation of nNOS and eNOS (endothelial nitric oxide synthase) were studied by Western blot analysis. Immunofluorescence was used to examine the localization of nNOS and eNOS in the endothelial layer of the mesenteric artery. The vasodilator effect of ACh is strongly impaired in mesenteric arteries of DOCA-salt-hypertensive mice. Non-selective inhibition of NOS sharply reduced the effect of ACh in both DOCA-salt-hypertensive and sham mice. Selective inhibition of nNOS and catalase led to a higher reduction in the effect of ACh in sham than in DOCA-salt-hypertensive mice. Production of H2O2 induced by ACh was significantly reduced in vessels from DOCA-salt-hypertensive mice, and it was blunted after nNOS inhibition. The expression of both eNOS and nNOS was considerably lower in DOCA-salt-hypertensive mice, whereas phosphorylation of their inhibitory sites was increased. The presence of nNOS was confirmed in the endothelial layer of mesenteric arteries from both sham and DOCA-salt-hypertensive mice. These results demonstrate that endothelial dysfunction in the mesenteric arteries of DOCA-salt-hypertensive mice is associated with reduced expression and functioning of nNOS and impaired production of nNOS-derived H2O2 Such findings offer a new perspective for the understanding of endothelial dysfunction in hypertension.
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Grazielle C
authors.initials: GC
authors.lastname: Silva
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Josiane F
authors.initials: JF
authors.lastname: Silva
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Thiago F
authors.initials: TF
authors.lastname: Diniz
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Lemos
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil sfcortes@icb.ufmg.br.
authors.forename: Steyner F
authors.initials: SF
authors.lastname: Cortes
mesh_terms: D000818:Animals; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; D009569:Nitric Oxide; D064791:Desoxycorticosterone Acetate; D006861:Hydrogen Peroxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: endothelial dysfunction; hydrogen peroxide; hypertension; neuronal nitric oxide synthase; resistance arteries