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A monoclonal antibody to gastrin was used to study the role of circulating gastrin in mediating insulin-stimulated acid output. On separate days, seven adult dogs with chronic gastric fistulas were pretreated i.v. with either 1) 7 mg of a gastrin monoclonal antibody (mAb 28.2); 2) 12.5 micrograms/kg atropine; 3) mAb 28.2 and atropine together; or 4) vehicle (0.1% canine serum albumin in 0.15 M NaCl). Thirty minutes later, acid secretion was stimulated by insulin (0.5 U/kg, i.v.), followed in 2 h by a 1-h infusion of histamine (40 micrograms/kg/h, i.v.). Acid output (mmol/15 min) in gastric effluent collected through the gastric fistula was determined by titration with 0.2 N NaOH to pH 7.0. Plasma gastrin was measured by radioimmunoassay. Plasma glucose was measured by a glucose oxidase method on an auto analyzer. Insulin induced a profound hypoglycemia (55 +/- 8 mg/dl) that coincided with a marked increase in acid output to 7.1 +/- 0.6 mmol/30 min by 45 min after injection. MAb 28.2 pretreatment and atropine pretreatment reduced insulin-stimulated acid outputs to 2.7 +/- 0.7 mmol/30 min and to 0.6 +/- 0.2 mmol/ 30 min, respectively. Acid output after combined pretreatment (0.5 +/- 0.2 mmol/30 min) was not significantly different than after atropine alone. Histamine-stimulated acid output (15.8 +/- 2.5 mmol/30 min) was not significantly reduced by any pretreatment. Insulin injection increased circulating gastrin concentrations to 32 +/- 7 fmol/ml, which was not significantly affected by atropine (39 +/- 9 fmol/ml). This study demonstrates that, in dogs, a significant part of insulin-stimulated acid secretion is mediated by circulating gastrin.

Cholecystokinin is a principal mediator of intestinal fat-induced inhibition of gastric acid secretion, indicating that it is an important physiological enterogastrone. Cholecystokinin has been shown to inhibit acid secretion by activation of type A CCK receptors and through a mechanism involving somatostatin. In the present study, we investigated the possibility that these two mechanisms are directly related such that activation of type A CCK receptors by CCK causes the release of somatostatin. We tested this hypothesis in vivo in a study of CCK-stimulated release of somatostatin in dogs and in vitro in a study of CCK-stimulated release of somatostatin from an enriched culture of canine fundic D cells. In dogs, IV infusion of CCK (50 pmol/kg/h, IV) significantly increased circulating somatostatin concentrations above basal. Further, systemic administration of somatostatin MAb F(ab)1 fragments of a somatostatin monoclonal antibody prevented most of CCK-induced inhibition of meal-stimulated acid secretion. In canine fundic D cells in culture, CCK-stimulated somatostatin release was blocked in a dose-dependent fashion by application of a type A CCK receptor antagonist. This study indicates that CCK activates type A CCK receptors to release somatostatin from canine fundic mucosal D cells, and accounts for somatostatin-dependent CCK-induced inhibition of acid secretion.