We tested the hypothesis that intraluminal oxygenation can prevent increased gut mucosal permeability to a hydrophilic solute caused by mesenteric ischemia/reperfusion (I/R). Studies were performed using pentobarbital-anesthetized immature pigs. Paired 20 cm segments of ileum were perfused intraluminally at 200 ml/hr with either nitrogenated or oxygenated 37 degrees C Ringer's lactate. Beginning at T = -90 min, fluorescein disodium acetate was infused intravenously (12.5 mg/kg bolus, then 12.5 mg/kg/hr). Permeability was assessed by calculating the plasma-to-lumen clearance of fluorescein. Five pigs were subjected to complete mesenteric ischemia (T = 0-120 min) followed by reperfusion (T = 120-270 min). In nitrogenated segments, I/R resulted in a 1015 +/- 195% increase in fluorescein clearance (P < 0.01 vs baseline). In contrast, the increase in fluorescein clearance induced by I/R in oxygenated segments was only 264 +/- 63% (P < 0.01 vs baseline). Intraluminal oxygenation afforded significant (P < .01) protection against I/R-induced mucosal hyperpermeability at all time points from T = 150-270 min. Histologic sections revealed complete villous epithelial denudation in nitrogenated segments, whereas the mucosal epithelium was largely intact in oxygenated segments. After reperfusion, mucosal ATP levels normalized in oxygenated segments, but there was only partial recovery of ATP levels in nitrogenated segments. These data indicate that intraluminal oxygenation ameliorates mucosal hyperpermeability induced by I/R.