Dose-related reduction of intestinal cytochrome a,a3 induced by endotoxin in rats

Dose-related, endotoxin-induced changes in oxidative metabolism were investigated in vivo using near-infrared spectrophotometry. Sixty fasted male Sprague-Dawley rats were randomly allocated to groups (N = 10 each) receiving saline, 0.08, 0.3, 1.25, 5, or 20 mg/kg Escherichia coli endotoxin by i.v. bolus (1 ml/kg volume). Isoflurane anesthesia with controlled ventilation was used for surgery and the subsequent collection of hemodynamic and metabolic data. Approximately half the length of the small intestine was exteriorized for continuous spectrophotometric monitoring of tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and mitochondrial cytochrome a,a3 (AA3) redox state. Hemodynamic parameters included arterial and central venous pressures, cardiac output, and superior mesenteric artery blood flow (SMAF). Intestinal AA3 exhibited a marked and sustained shift toward reduction in those groups (1.25, 5, and 20 mg/kg) which developed significant blood pressure and blood flow decreases. However, the AA3 reduction did not seem to reflect tissue hypoxia, since 1) the simultaneously measured tissue HbO2 levels remained essentially constant, 2) the AA3 redox shift did not reverse upon recovery of intestinal blood flow in the 1.25 mg/kg group, which exhibited only a transient decrease in SMAF, and 3) systemic oxygen consumption was unchanged in any group. Endotoxin-induced lethality was tested in six separate groups (N = 10 each) and was significant (60%) only in the 20 mg/kg group. These results suggest that endotoxin may induce a direct (or rapidly mediated indirect) impairment of cellular oxidative phosphorylation.