title: Nitric oxide from inducible nitric oxide synthase sensitizes the inflamed aorta to hypoxic damage via respiratory inhibition.
abstract: We tested whether nitric oxide (NO) could synergize with hypoxia to induce damage to the aorta isolated from rat. We found that 4 h of mild hypoxia (5% O2) caused substantial necrosis of isolated rat aortae (measured as lactate dehydrogenase release) if inducible NO synthase (iNOS) had previously been induced by endotoxin plus interferon-gamma. Mild hypoxia caused no significant necrosis in the absence of this inflammatory activation, and inflammatory activation caused little damage at a higher oxygen levels (21% oxygen). An iNOS inhibitor (1400W) prevented the necrosis induced by inflammation plus mild hypoxia, whereas the NO donor diethylenetriamine (DETA)/NO adduct, 0.5 mM) greatly sensitized the noninflammed aorta to necrosis induced by mild hypoxia. NO inhibited aortic respiration to a greater degree at lower oxygen concentrations, consistent with NO inhibition of cytochrome oxidase in competition with oxygen. A specific inhibitor of mitochondrial respiration, myxothiazol, caused necrosis of aortae over a similar time course to NO. DETA/NO plus mild hypoxia-induced cell death was substantially reduced by a glycolytic intermediate 3-phosphoglycerate, suggesting that necrosis resulted from energy depletion secondary to respiratory inhibition. This NO-induced sensitization of aorta to mild hypoxia may be important in sepsis and other pathologies where iNOS is expressed.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
authors.forename: Vilmante
authors.initials: V
authors.lastname: Borutaite
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001011:Aorta / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D005988:Glyceric Acids / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis; D000860:Hypoxia; D007249:Inflammation; D008297:Male; D008689:Methacrylates; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010100:Oxygen / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D005988:Glyceric Acids; D008689:Methacrylates; D020030:Nitric Oxide Donors; D011073:Polyamines; D013844:Thiazoles; C005391:diethylenetriamine; D009569:Nitric Oxide; C030517:myxothiazol; C005156:3-phosphoglycerate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010100:Oxygen