The present study was designed to determine whether somatostatin secretion induced by histamine or pentagastrin in the isolated luminally perfused mouse stomach was a direct effect of the secretagogues on gastric somatostatin cells or an indirect effect mediated by the increase in luminal acidity. Perfusion of the lumen with exogenous acid (80-480 nmol/min) caused an increase in somatostatin secretion in proportion to the increase in luminal acidity. The increase in somatostatin secretion was resistant to tetrodotoxin and attained maximal levels (61.6% +/- 8.7% above basal level) similar to those elicited by maximal doses of secretagogues. Conversely, neutralization of basal acid secretion with bicarbonate (20-160 nmol/min) caused a decrease in somatostatin secretion in proportion to the decrease in luminal acidity. Similarly, neutralization of the secretagogue-induced increments in acid secretion with bicarbonate or inhibition of the increments with cimetidine abolished the corresponding increments in somatostatin secretion. It is proposed that acid-induced release of somatostatin in proximity to parietal cells serves as a negative feedback mechanism restraining acid secretion.