We measured transmucosal potential difference (PD) of the stomach in anesthetized rats before, during, and after hemorrhagic shock, and investigated the effects of various drugs on the PD and gastric lesion during this period. After hemorrhagic shock, there was a decrease of PD and an increase of luminal pH in the saline-perfused stomach, the degree of these changes being dependent on a fall in the arterial blood pressure. The graded reduction of PD in response to hemorrhagic shock was similarly observed in the acid-perfused stomach as in the saline-perfused one. However, gastric lesions developed only in the former, and a significant correlation was found between the lesion index and the fall in blood pressure, the reduction in PD, or the concentration of HCl as the perfusate. Subcutaneously administered propantheline bromide (30 mg/kg) or cimetidine (100 mg/kg) had no effect on gastric lesion and PD reduction caused by hemorrhagic shock. These lesions were significantly inhibited by 16,16-dimethyl prostaglandin E2 (10 micrograms/kg) or sulindac (100 mg/kg), a scavenger of OH., and aggravated by indomethacin (1 mg/kg), with less effect on the PD reduction. Intravenous infusion of NaHCO3 (0.5 M) also significantly prevented the lesion with a concomitant suppression of the PD reduction in response to hemorrhagic shock, but these effects were significantly reversed by pretreatment of the animals with acetazolamide (50 mg/kg). These results indicate that during hemorrhagic shock the PD may largely reflect the impairment of mucosal blood flow and may be used as an indicator of mucosal vulnerability to acid, gastric lesions develop only in the presence of exogenous acid, and production of prostaglandins and superoxide radicals may be involved in the pathogenesis of gastric lesions.