Orsi, Antonia; (2000) Physiological regulation and pathological inhibition of tissue respiration by nitric oxide. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Long-term exposure of Jurkat, L929 and J774 cells to exogenous NO inhibits cellular respiration at the level of complex IV that is reversed by oxyHb and at the level of complex I that is not reversed by oxyHb. Long-term exposure of NO to the cells causes a decrease in reduced glutathione concentration that precedes the inhibition at the level of complex I. This inhibition is reversed by addition of reduced glutathione or cold light, suggesting that S- nitrosylation of thiols is necessary for the activity of the enzyme. Furthermore, long-term exposure of the cells to NO decreases oxygen utilisation due to two distinct actions, one being the inhibition of cellular oxygen consumption and the other, the generation of a hypoxic microenvironment due to the oxygen consumption by the extracellular medium. Inhibition of basal NO, with a NO synthase inhibitor, increases cellular respiration in iNOS mutant, iNOS and eNOS wild type, but not in eNOS mutant mice. Administration of a low dose of endotoxin to the mice leads to a short-term generation of NO associated with a short-term inhibition of mitochondrial respiration resulting in non-lethal shock. Whereas administration of a high dose of endotoxin leads to a sustained generation of NO accompanied by a sustained inhibition of mitochondrial respiration, at the level (at least in part) of complex I, resulting in lethal shock. These results suggest that NO can be considered as a physiological regulator and a pathological inhibitor of tissue respiration. The basal release of small amounts of NO acts as a regulating mechanism, whereby cells respond to changes in their environment and regulate ATP production. By contrast the generation of high concentrations of NO over a sustained period decreases reduced glutathione concentration and pathologically inhibits cellular respiration leading to multiple organ failure and ultimately death.

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