Mitochondrial NO in endotoxemia

ALVAREZ SILVIA; BOVERIS, ALBERTO

Proceedings of the Biennial Meeting of the SFRR

Medimond SRL

Lugar: Bologna; Año: 2004; p. 133 - 136

Septic shock constitutes a paradigm of acute whole body inflammation, with massive increases of NO and of inflammatory cytokines in biological fluids, with systemic damage to vascular endothelium, and with impaired tissue (and whole body) respiration, this latter despite adequate oxygen supply [1]. Septic shock, in animals and humans, is initiated by the lipopolisaccharide (LPS) endotoxin; which is able to initiate a massive inflammatory response. The concept of a bioenergetic failure due to muscle mitochondrial dysfunction as part of the pathogenic mechanism of septic shock was introduced about 35 years ago. This phenomenon is now considered as derived from increased NO levels in both the vascular smooth muscle and in skeletal and heart muscle. Mitochondria isolated from vascular smooth muscle and skeletal and heart muscle, exhibit impaired respiration due to inhibition of electron transfer and oxidative phosphorylation [2, 3]. These observations are explained by an excessive production of NO by mtNOS [2], which leads to: a) the reversible O2-competitive inhibition of cytochrome oxidase (complex IV) by NO, and b) the inhibitory effect of NO and ONOO- on ubiquinol-cytochrome c reductase (complex III), and the inhibitory effect of ONOO- on NADH-ubiquinone reductase (complex I). .Experimental endotoxic shock was observed to produce a marked increase in the activity of rat diaphragm mtNOS [2]. This enzyme is located in the inner mitochondrial membrane [4].The aims of this study were to determine in heart and diaphragm mitochondria of LPS-endotoxemic rats: a) mtNOS activity and the relationships between NO metabolism and oxidative metabolism; b) the responses of Mn-superoxide dismutase and catalase to endotoxic shock and their impact on O2·- and H2O2 metabolism; and c) the steady state concentrations of the main chemical species currently understood as responsible of the molecular mechanism of endotoxic and septic shock: NO, O2·-, H2O2, and ONOO-.