OBJECTIVE: To investigate whether the vascular dysfunction in endotoxic shock is associated with inhibition of the veno-arterial response of the superior mesenteric artery. DESIGN: Prospective, concurrent trial. SETTING: Animal laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Two groups of pigs were anesthetized with ketamine and pentobarbital, mechanically ventilated, and hemodynamically monitored. One group (n = 8) was challenged with Escherichia coli endotoxin (30 micrograms/kg iv), while the other group (n = 4) served as time controls. Portal vein pressure was transiently increased in a series of steps from baseline to 25 mm Hg by partially obstructing portal venous flow. MEASUREMENTS AND MAIN RESULTS: The effects of increases in portal pressure on superior mesenteric artery resistance, superior mesenteric artery fractional flow, and cardiac output were assessed. Under pre-endotoxin conditions, raising portal pressure induced an increase in superior mesenteric artery resistance, a decrease in superior mesenteric artery fractional flow, and no significant change in cardiac output (i.e., a normally regulating veno-arterial response). After endotoxin administration, raising portal pressure induced a decrease in superior mesenteric artery resistance, no change in superior mesenteric artery fractional flow, and a decrease in cardiac output (i.e., a dysregulated veno-arterial response). CONCLUSIONS: Under baseline conditions, a normally regulating veno-arterial response in the mesenteric vascular bed should minimize intestinal blood pooling with acute portal hypertension. Under conditions of endotoxemic shock, the dysregulation of the veno-arterial response could substantially contribute to blood pooling and edema formation in the intestinal vascular bed during septic shock. This phenomenon may account for many of the macro- and microcirculatory manifestations of septic shock.