title: Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen.
abstract: This study examined vascular function and the role of superoxide in mice that chronically express human renin (R+) and human angiotensinogen (A+). Responses of aortas from R+/A+ mice and from their normotensive littermates (RA- mice) were examined in vitro. Endothelium-dependent relaxation to acetylcholine was impaired in vessels from R+/A+ mice (e.g., maximal relaxation to 100 microM acetylcholine was 45 +/- 5% and 65 +/- 3% in R+/A+ and RA- mice, respectively; P < 0.05). Relaxation was also impaired to the endothelium-independent dilators authentic nitric oxide and nitroprusside in vessels from R+/A+ mice. Maximal vasorelaxation to the endothelium-independent, non-nitric oxide dilator papaverine was similar in R+/A+ and RA- mice. Incubation of vessels from R+/A+ mice with Tiron (1 mM), a superoxide scavenger, improved relaxation to acetylcholine, nitric oxide, and nitroprusside. In contrast, incubation with diethyldithiocarbamate (1 mM), an inhibitor of copper-containing SODs, reduced acetylcholine- and nitroprusside-induced relaxation in vessels from both R+/A+ and RA- mice. Basal superoxide levels, measured with lucigenin-enhanced chemiluminescence (5 microM lucigenin) and hydroethidine-based fluorescent confocal microscopy, were higher in vessels from R+/A+ mice and were Tiron and polyethylene glycol-SOD sensitive. These results suggest that increased superoxide contributes to impaired nitric oxide-mediated relaxation in this genetic model of chronic angiotensin II-dependent hypertension.
authors.affiliation: Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City 52242, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Didion
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Gary L
authors.initials: GL
authors.lastname: Baumbach
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology*; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000808:Angiotensinogen; D013481:Superoxides; D009569:Nitric Oxide; D004050:Ditiocarb; D010208:Papaverine; D013482:Superoxide Dismutase; D012083:Renin; D000109:Acetylcholine