In shocked animals, topical application of bile acids at low pH to gastric mucosa results in gross mucosal injury. Both systemic prostaglandins and isoproterenol reduce this injury, but side effects may limit their clinical usefulness. The purpose of this study was to determine the effect of topical pretreatment with isoproterenol and prostaglandin E2 on gastric mucosal injury induced by low concentrations of bile acid in shocked and normotensive rats. Mucosal injury was assessed by measuring net transmucosal ion fluxes (H+,K+) and luminal accumulation of DNA (DNAE), a sensitive and specific indicator of gastric mucosal cell exfoliation. In this model of mucosal injury, pretreatment with prostaglandin E2 or isoproterenol significantly and dose dependently decreased luminal hydrogen loss, potassium gain, and DNA accumulation in both shocked and normotensive animals. Thus, both topical prostaglandin E2 and isoproterenol reduce gastric mucosal injury caused by low concentrations of bile acid in shocked and normotensive rats, findings corroborated by histology. These findings provide a physiologic basis for the possible use of these agents as prophylaxis or treatment of stress gastritis and gastroduodenal ulcer in the critically ill patient.