Nitric oxide from inducible nitric oxide synthase sensitizes the inflamed aorta to hypoxic damage via respiratory inhibition.
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.
Borutaite
Vilmante
V
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
Moncada
Salvador
S
Brown
Guy C
GC
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
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