Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen.
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.
Didion
Sean P
SP
Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City 52242, USA.
Ryan
Michael J
MJ
Baumbach
Gary L
GL
Sigmund
Curt D
CD
Faraci
Frank M
FM
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
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