The pathophysiology of acute renal failure (ARF) in sepsis is only partly understood. In several animal models of septic ARF, no profound tissue hypoxia or decrease in microcirculatory Po-2 (mu Po-2) can be seen. We hypothesized that heterogeneity of microcirculatory oxygen supply to demand in the kidney is obscured when looking at the average mu Po-2 during endotoxemia. In 20 anesthetized and ventilated rats, MAP, renal blood flow (RBF), and creatinine clearance (CLcrea) were recorded. Renal mu Po-2 was measured by phosphorescence quenching, allowing measurement of mu Po-2 distributions. Five animals received a 1-h LPS infusion (10 mg kg(-1) h(-1)). In 5 rats, RBF was mechanically reduced to 2.1 +/- 0.2 mL min(-1). Five animals served as time control. LPS infusion significantly reduced RBF to 2.1 +/- 0.2 mL min(-1) and induced anuria. Average cortical mu Po-2 decreased from 68 +/- 4 to 52 +/- 6 mmHg, with a significant left shift in the cortical oxygen histogram toward hypoxia. This shift could not be observed in animals receiving mechanical RBF reduction. In these animals, CLcrea was reduced to 50%. An additional group of rats (n = 5) received fluid resuscitation. In these animals, RBF was restored to baseline, CLcrea increased approximately 50%, and the cortical microcirculatory hypoxic areas disappeared after resuscitation. In conclusion, endotoxemia was associated with the occurrence of cortical microcirculatory hypoxic areas that are not detected in the average Po-2 measurement, proving the hypothesis of our study. These observations suggest the involvement of hypoxia in the pathogenesis of endotoxemia-induced ARF.