This study evaluated the effects of topical isoproterenol, a beta-adrenergic agonist, on the morphologic damage produced in the gastric mucosa by ethanol. The orogastric instillation of 100% ethanol in rats resulted in gross lesion formation and deep histologic injury in the gastric mucosa. Animals pretreated with oral isoproterenol (50 micrograms/kg, 500 micrograms/kg, 50 mg/kg) showed dose-dependent protection from both the gross and the histologic mucosal injury (P less than 0.01, ANOVA). Pretreatment with propranolol (2 mg/kg/sec) but not indomethacin (5 mg/kg/sec) blocked this protective effect. Isoproterenol had no effect on ethanol-induced mast cell degranulation as both mucosal and submucosal mast cell counts were significantly and equally decreased in all groups treated with 100% ethanol (P less than 0.05). These findings show that topical isoproterenol protects the rat gastric mucosa from both the gross and the histologic injury caused by 100% ethanol. This protection is mediated by a beta-adrenergic receptor mechanism as it can be blocked by prior treatment with propranolol, but does not involve stabilization of mucosal or submucosal mast cell membranes.