Somatostatin is known to inhibit gastric acid secretion via both inhibition of histamine release from gastric enterochromaffin-like cells and direct inhibition of parietal cell function. We tried to clarify which of these two mechanisms plays a more important role in the inhibition of gastric acid section by somatostatin using isolated mouse stomach preparations. The gastric acid secretion stimulated by histamine was not inhibited by pretreatment with somatostatin (1 muM), but somatostatin abolished acid secretion induced by 4-[[[(3-chlorophenyl)amino]carbonyl]oxyl-N,N,N-trimethyl-2-butynyl-1-aminium chloride (McN-A-343), a muscarinic M-1 receptor agonist. In addition, the histamine-H-2 receptor antagonist famotidine also completely inhibited the secretion stimulated by McN-A-343. Similarly, pretreatment with both somatostatin and famotidine completely abolished pentagastrin-induced acid secretion. Somatostatin partially inhibited the acid secretion stimulated by bethanechol. The late sustained acid secretion induced by bethanechol was reduced more strongly by somatostatin than the initial peak secretion. In addition, somatostatin had no effect on the transient increase in bethanechol-induced acid secretion in famotidine-pretreated preparations. Somatostatin had no effect on basal histamine secretion in isolated mouse stomach preparations, but markedly reduced histamine release induced by McN-A-343 and bethanechol. The present study showed that the acid secretory response via the endogenous histamine-mediated pathway was inhibited by somatostatin, but the response to a direct activation of gastric parietal cells was not. These results suggest that the inhibition of histamine release from enterochromaffin-like cells plays a more important role in the inhibition of gastric acid secretion by somatostatin than the direct inhibition of parietal cells. In addition, somatostatin inhibited the sustained acid secretion more strongly than the initial peak secretion after the cholinergic stimulation. (C) 2002 Elsevier Science B.V All rights reserved.