ET-1 is a potent vasoconstrictor peptide with multiple biologic effects. Since ET-1 stimulates the inflammatory cascade and promotes intestinal vasoconstriction, we hypothesized that endogenous ET-1 plays an important role in endotoxin and hypoxia-induced intestinal injury. Male Sprague Dawley rats weighing 150-250 grams were anesthetized with pentobarbital and treated in the following groups: 1) control (ventilated with 21% O2), 2) LPS (2mg/kg i.v.) + H (ventilated with 10% O2), and 3) ET-1 receptor blockade, BQ123 (1 mg/kg i.v.) + LPS + H. Mean arterial blood pressure and superior mesenteric artery (SMA) blood flow were continuously recorded, and at 90 minutes an arterial blood gas was obtained, the rats euthanized and intestine harvested for gross and histological analysis. The mean arterial pressure for controls decreased to 87.1% of baseline over 90 min, whereas MAP in group 2 and group 3 decreased to 30.9% and 33.8% of baseline, respectively. Similarly, the SMA blood flow in controls fell to 68.9% of baseline, while group 2 and 3 showed more pronounced intestinal vasoconstriction (SMA flow 32.3% and 38.8% of baseline). At 90 minutes control animals had normal acid-base balance and oxygenation (mean pH 7.341, pO2=141 torr), while groups 2 and 3 developed acidosis and hypoxemia (group 2: pH 7.04, pO2 70; group 3: pH 7.10, pO2 78). However, gross inspection of the intestine was normal in the controls, showed moderate to severe damage in 5/6 animals of group 2, and mild damage to all specimens in group 3. Histological data was scored as follows: 0-normal intestine; 1+-mild epithelial sloughing; and 2+-mid-villous necrosis. The control group had normal or minimal damage in all animals, group 2 showed 2+ damage in 5 out of 6 animals, and group 3 ranged from 0 to 1+ in 6 out of 6 animals (p < 0.05 compared to group 2). These results suggest that BQ123 pretreatment prevents intestinal injury without affecting the hemodynamic decompensation following the stress with LPS and hypoxia in this protocol. We speculate that BQ123 may prevent intestinal damage by blocking the inflammatory cascade.