title: Protection against lipopolysaccharide-induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice.
abstract: Endothelial dysfunction is a characteristic of, and may be pathogenic in, inflammatory cardiovascular diseases, including sepsis. The mechanism underlying inflammation-induced endothelial dysfunction may be related to the expression and activity of inducible nitric oxide synthase (iNOS). This possibility was investigated in isolated resistance (mesenteric) and conduit (aorta) arteries taken from lipopolysaccharide (LPS)-treated (12.5 mg/kg i.v.) or saline-treated iNOS knockout (KO) and wild-type (WT) mice. LPS pretreatment (for 15 h, but not 4 h) profoundly suppressed responses to acetylcholine (ACh) and significantly reduced sensitivity to the NO donor spermine-NONOate (SPER-NO) in aorta and mesenteric arteries of WT mice. This effect was temporally associated with iNOS protein expression in both conduit and resistance arteries and with a 10-fold increase in plasma NOx levels. In contrast, no elevation of plasma NOx was observed in LPS-treated iNOS KO animals, and arteries dissected from these animals did not express iNOS or display hyporeactivity to ACh or SPER-NO. The mechanism underlying this phenomenon may be suppression of eNOS expression, as observed in arteries of WT animals, that was absent in arteries of iNOS KO animals. These results clearly demonstrate that iNOS induction plays an integral role in mediation of the endothelial dysfunction associated with sepsis in both resistance and conduit arteries.
authors.affiliation: Clinical Pharmacology, Barts and The London, Queen Mary's School of Medicine, London EC1M 6BQ, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Chauhan
authors.forename: G
authors.initials: G
authors.lastname: Seggara
authors.forename: P A
authors.initials: PA
authors.lastname: Vo
authors.forename: R J
authors.initials: RJ
authors.lastname: Macallister
authors.forename: A J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: A
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005838:Genotype; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D009589:Nitrogen Oxides; D009638:Norepinephrine / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009589:Nitrogen Oxides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D000109:Acetylcholine; D009638:Norepinephrine