title: Role of angiotensin II in endothelial dysfunction induced by lipopolysaccharide in mice.
abstract: Endotoxin [or lipopolysaccharide (LPS)] increases levels of superoxide in blood vessels and impairs vasomotor function. Angiotensin II plays an important role in the generation of superoxide in several disease states, including hypertension and heart failure. The goal of this study was to determine whether the activation of the renin-angiotensin system contributes to oxidative stress and endothelial dysfunction after endotoxin. We examined the effects of enalapril (an angiotensin-converting enzyme inhibitor) or L-158809 (an angiotensin receptor blocker) on increases of superoxide and vasomotor dysfunction in mice treated with LPS. C57BL/6 mice were treated with either enalapril (60 mg.kg(-1).day(-1)) or L-158809 (30 mg.kg(-1).day(-1)) for 4 days. After the third day, LPS (10-20 mg/kg) or vehicle was injected intraperitoneally, and one day later, vasomotor function of the aorta was examined in vitro. After precontraction with PGF(2alpha), the maximal responses to sodium nitroprusside were similar in the aorta from normal and LPS-treated mice. In contrast, the relaxation to acetylcholine was impaired after LPS (54 +/- 5% at 10(-5), mean +/- SE) compared with vessels treated with vehicle (88 +/- 1%; P < 0.05). Enalapril improved (P < 0.05) relaxation in response to acetylcholine to 81 +/- 6% after LPS. L-158809 also improved relaxation in response to acetylcholine to 77 +/- 4% after LPS. Superoxide (measured with lucigenin and hydroethidine) was increased (P < 0.05) in aorta after LPS, and levels were reduced (P < 0.05) following enalapril and L-158809. Thus, after LPS, enalapril and L-158809 reduce superoxide levels and improve relaxation to acetylcholine in the aorta. The findings suggest that activation of the renin-angiotensin system contributes importantly to oxidative stress and endothelial dysfunction after endotoxin.
authors.affiliation: Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Lund
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brooks
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D013777:Tetrazoles; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009599:Nitroprusside; C070967:L 158809; D004656:Enalapril; D000109:Acetylcholine