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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3726    most recent 01116.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lund, D. D. Articles by Heistad, D. D. PubMed PubMed Citation Articles by Lund, D. D. Articles by Heistad, D. D.

Role of angiotensin II in endothelial dysfunction induced by lipopolysaccharide in mice

Departments of ¹Internal Medicine and ²Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, and ³Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 25 September 2007 ; accepted in final form 22 October 2007

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 PGF₂, 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.

endotoxin; enalapril; L-158809; endothelial function