Clinical observations reveal that alcohol intake is associated with an increase in upper gastrointestinal hemorrhage requiring hospitalization and that nitroglycerin or long-acting nitrates lower this risk. Nitroglycerin, a gastric vasodilator that can increase gastric fluid volume, protects the rodent stomach against damage, including that caused by 70% ethanol. Blockade of alpha(2)-adrenoceoptors attenuates gastric protection by intragastric nicotine against 40% ethanol. We tested the hypothesis that the protective effect of nitroglycerin is mediated by an increase in gastric fluid volume and alpha(2)-adrenoceoptors. Nitroglycerin, 5 mg/kg, vehicle, or acidified ethanol was administered intragastrically. In study 1 acidified ethanol-induced mucosal injury was measured. In study 2 the effect of increasing gastric volume (1 ml/kg) on mucosal injury was assessed. In study 3 the effect of yohimbine (alpha(2)-adrenoceoptor antagonist), 5 mg/kg subcutaneously, on the nitroglycerein-mediated protective effect was determined. Results showed that nitroglycerin significantly attenuated the number and length of mucosal lesions induced by acidified ethanol. Increase in gastric fluid volume by exogenously administered saline did not alter the protective effect. Yohimbine blocked the nitroglycerin-mediated protection. These experimental data are consistent with the observation that nitrates lower the risk of ethanol-induced gastrointestinal complications. alpha(2)-Adrenoceoptors are responsible in part for the protective effect of nitroglycerin.