Studies in isolated mouse stomach showed that bombesin releases somatostatin. We characterized the effects of exogenous bombesin on gastric acid secretion in mice and determined the involvement of somatostatin and somatostatin receptor type 2 (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. Gastric acid secretion was monitored under basal and pentagastrin-, histamine- or bethanechol-stimulated conditions in urethane-anaesthetized mice. Bombesin (10-40 micro g kg-1 h-1) and somatostatin-14 (20 micro g kg-1 h-1) were infused I.V. 10 and 30 min after PRL-2903 or somatostatin antibody pretreatment, respectively. Urethane-anaesthetized wild-type mice had low basal acid secretion (0.12 +/- 0.01 micro mol (10 min)-1) compared with SSTR2 knockout mice (1.43 +/- 0.10 micro mol (10 min)-1). Somatostatin antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. In wild-type mice, bombesin inhibited secretagogue-stimulated acid secretion in a dose-dependent manner, and somatostatin-14 inhibited pentagastrin-stimulated secretion. In wild-type mice pretreated with somatostatin antibody or PRL-2903 and in SSTR2 knockout mice, bombesin and somatostatin-14 I.V. infusion did not alter the increased gastric acid secretion. These results indicate that, in mice, bombesin inhibits gastric acid secretion through the release of somatostatin and the activation of SSTR2. These observations strengthen the important role of SSTR2 in mediating somatostatin inhibitory actions on gastric acid secretion.