Bombesin or gastrin-releasing peptide prevents gastric injury by an unknown mechanism. Since exogenous gastrin is a gastroprotective agent, this study was undertaken to test the hypothesis that gastroprotection by bombesin involves release of endogenous gastrin. Subcutaneous bombesin (10-100 μg/kg) dose dependently reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orogastric acidified ethanol (150 mM hydrochloric acid-50% ethanol). Blockade of type A cholecystokinin receptors with intraperitoneal MK-329 (1 mg/kg) reversed intravenous cholecystokinin (5 nmol/kg)-induced gastroprotection, but not that of bombesin. In contrast, intraperitoneal type B cholecystokinin (gastrin) receptor blockade with L-365,260 (25 mg/kg) diminished the protective actions of both subcutaneous bombesin (100 μg/kg) and intravenous gastrin (25 pmol/kg). In additional studies, subcutaneous bombesin (10-100 μg/kg) dose dependently increased serum gastrin levels (radioimmunoassay). Both the gastroprotective actions of bombesin and bombesininduced gastrin release were enhanced following immunoneutralization of endogenous somatostatin with intraperitoneal somatostatin antibody (2 mg). These data indicate that bombesin prevents gastric injury primarily by release of endogenous gastrin and both effects are modified by endogenous somatostatin.