title: Inhibition of mitochondrial respiration during early stage sepsis.
abstract: It is known that nitric oxide (NO) is produced in response to a septic insult such as bacterial invasion and that overproduction of NO can have serious debilitating consequences. The mechanism by which NO causes damage at the cellular level is less clear. We have therefore studied the response to a septic insult in an anaesthetised spontaneously breathing Sprague-Dawley rat model. Six rats were given either an intravenous infusion of bacterial cell wall lipopolysaccharide (LPS, 5 mg/kg) or saline control over 1 hour. For electron paramagnetic resonance (EPR) studies, blood samples were collected every hour for a further two hours and liver tissue samples were collected postmortem. Measurement was also made of PaO2, blood pressure, base deficit, aortic and renal blood flow and hepatic microvascular pO2 (using porphyrin phosphoresence). Tissue samples were also collected for mitochondrial complex activity analysis. After the administration of LPS blood pressure, blood flow and microvascular PO2 were diminished and the base deficit increased. In addition a clear difference was observed by EPR between control and insulted blood and tissue samples. A large heam-nitrosyl signal is observed as well as an increase in the signal at g = 1.94, corresponding to the iron-sulphur centres of complex I becoming more reduced. However, no significant difference was observed for any of the mitochondrial complex activities. The effect of the NO produced was to depress the circulatory variables and increase base deficit, combined with a reduced oxygen consumption this implies an impairment of normal aerobic respiration. This was supported by increased iron-sulphur signals observed by EPR indicating a blockage in the mitochondrial redox chain with the subsequent accumulation of electrons. As no effect was observed in the mitochondrial complex activities this indicates that this inhibition is reversible in early stage sepsis. We conclude that nitric oxide produced in response to a septic insult can inhibit mitochondria causing an impairment of oxygen utilisation by aerobic respiration.
authors.affiliation: Dept. Biological Sciences, University of Essex, Colchester, Essex CO4 3SQ, UK.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.forename: Chris E
authors.initials: CE
authors.lastname: Cooper
authors.forename: Ray
authors.initials: R
authors.lastname: Stidwill
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D006439:Hemodynamics; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*