BACKGROUND: The role of nitric oxide in intestinal ischemia-reperfusion is unclear-some studies link it to the harmful effects of ischemia-reperfusion, while others report it to be protective. We propose that nitric oxide levels diminish in the reperfusion period in conjunction with the onset of increased capillary permeability. The aim of this study is to determine the effect of supplementing nitric oxide synthase with its substrate, l-arginine, on development of local mucosal injury and systemic capillary leak. MATERIALS AND METHODS: Rats underwent 30 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. The vehicle groups received l-arginine either intravenously (4 mg/kg/min) or into the intestinal lumen. The intravenous groups received l-arginine either before the ischemic event or after 30 min of reperfusion. Capillary leak in the gut and lung were measured, as were degree of mucosal injury and number of infiltrating neutrophils. Appropriate controls were performed. RESULTS: Thirty minutes of mesenteric ischemia followed by 4 h of reperfusion significantly increased gut and lung leak, neutrophil infiltration, and the severity of mucosal injury. l-Arginine given iv prior to ischemia inhibited lung leak, mucosal injury, and neutrophil infiltration. When arginine was given during the reperfusion period, lung leak and neutrophil infiltration but not mucosal injury were reduced. Intraluminal l-arginine reduced mucosa injury, but had no effect on capillary leak. CONCLUSIONS: Supplementation with l-arginine enhances NO production, resulting in reduced systemic endothelial dysfunction. This may act as a useful clinical adjunct in the management of trauma patients in preventing the development of ARDS and multiple organ failure.