Clinically, hypermetabolism of the liver accompanies the systemic response associated with trauma and sepsis. Although increased metabolism is generally considered a beneficial response, a markedly increased hepatic oxygen consumption (HVO2) may be associated with adverse consequences such as induction of centrilobular hypoxia. We studied the effects of lactate and glucagon as inducers of increased HVO2 in the isolated perfused rat liver to determine if hepatic functional derangements could be precipitated by these trauma-associated factors at high metabolic rates. HVO2 rose by 27%, 52%, and 70% in response to 5 mM lactate/1 mM pyruvate, 20 nM glucagon, or both, respectively. In response to these stimuli at a fixed perfusion rate, hepatic venous oxygen saturation declined to 48 +/- 4% at the highest HVO2, and this was associated with a reduced hepatic adenosine triphosphate content and fibrinogen secretion. These findings indicate that hepatic metabolic disturbances can result from hepatocellular hypoxia due to increased HVO2.