OBJECTIVE: To investigate, during endotoxic shock, the effect of a treatment of norepinephrine (NE) administration on the distribution of blood flow and adenosine triphosphate (ATP) content in the intestinal wall. DESIGN: Randomized controlled trial. SETTING: Animal laboratory. SUBJECTS: Domestic pigs. INTERVENTION: A total of 18 pigs were anesthetized with ketamine and pentobarbital, mechanically ventilated, hemodynamically monitored, and then challenged with a continuous infusion of Escherichia coli endotoxin (ET) (15 microg/kg) for 2 hrs. Three groups of six animals were studied; one served as time control, one group received ET and fluid resuscitation, and a third group received ET, fluid resuscitation, and a perfusion of NE to maintain constant mean arterial pressure (MAP). MEASUREMENTS AND MAIN RESULTS: Cardiac output, mesenteric arterial blood flow, MAP, pulmonary pressure, and portal pressure were measured. Intestinal mucosal intracellular pH (pHi) was determined with saline-filled balloon tonometers. Tissue blood flows to the intestinal mucosa and to the muscular layer were independently measured with fluorescent microspheres, using the arterial reference sample method. Measurements were performed before and 3 hrs after the start of the ET challenge. At the end of the experiments, muscularis and mucosal samples were quickly frozen for further enzymatic ATP measurements. ET administration with fluid resuscitation induced a distributive shock with increased mucosal blood flow and decreased muscularis blood flow, whereas pHi decreased and mucosal ATP content was significantly lower than in the control group. In the group receiving ET plus NE, MAP remained constant, mucosal blood flow did not increase, and mucosal ATP content was equal to the time control group. Meanwhile, mucosal acidosis was not prevented. CONCLUSIONS: Normodynamic endotoxic shock may induce an alteration in mucosal oxygenation, despite an increased tissue blood flow. A treatment of NE combined with fluid resuscitation has complex effects on tissue blood flow, ATP content, and pHi.