Role of Increased Production of Superoxide Anions by NAD(P)H Oxidase and Xanthine Oxidase in Prolonged Endotoxemia

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Abstract
—Superoxide anions (O2−) are supposedly involved in the pathogenesis of endothelial dysfunction. We investigated whether the enhanced formation of O2− is involved in the attenuation of endothelium-dependent relaxation induced by lipopolysaccharide (LPS). Rats were injected with LPS (10 mg/kg IP), the aorta was removed after 12 or 30 hours, and generation of O2−, H2O2, and ONOO− was measured using chemiluminescence assays. Protein tyrosine nitration and expression of xanthine oxidase (XO), NAD(P)H oxidase, and manganese superoxide dismutase were determined by Western or Northern blotting, and endothelium-dependent relaxation in aortic rings was studied. LPS treatment increased vascular O2− (from 35±2 cpm/ring at baseline to 166±21 cpm/ring at 12 hours and 225±16 cpm/ring at 30 hours) and H2O2 formation, which was partially sensitive to the NAD(P)H oxidase inhibitor diphenylene iodonium at both time points studied and to the XO inhibitor oxypurinol only 30 hours after LPS treatment. Expression of XO...