Somatostatin-28 and somatostatin-14, secretion and function in the canine gastrointestinal tract

grantor: University of TorontoThere are two circulating biologically active forms of somatostatin, somatostatin-28 (S-28) and somatostatin-14 (S-14). Previous studies examining somatostatin release after nutrient ingestion did not determine whether measurements of total somatostatin are representative of responses by individual S-28 and S-14 components. The differential regulation by muscarinic mechanisms and gastric acid of S-28 and S-14 responses after solid meal ingestion and after insulin hypoglycemia were examined. The roles of S-28 and S-14 in the regulation of gastric acid and gastrin secretion were investigated and the somatostatin receptor subtype(s) (SSTR) mediating these effects were characterized. Meal ingestion increased plasma SLI three-fold and elevations of S-28 and S-14 were equivalent. Postprandial gastric acid secretion accounted for $\sim$50% of the rise in both S-28 and S-14. Whereas increased intraluminal acidity directly stimulated the rise in S-14, the S-28 response to gastric acid required cholecystokinin as a cofactor. Similarly, nutrient-independent vagal activation of S-14, but not S-28 secretion, was directly dependent upon increased gastric acid secretion. After nutrient administration, muscarinic excitatory pathways regulate S-28 secretion whereas muscarinic inhibitory pathways regulate S-14 secretion. This inhibition was amplified at neutral pH and was associated with an increase of meal-stimulated gastrin release. Reciprocal functional coupling of gastrin and S-14 secretion linked by muscarinic pathways was suggested by the finding that at neutral pH, muscarinic inhibition of gastrin was reversed by administration of a somatostatin antagonist. S-14, but not S-28, was shown to inhibit gastrin-stimulated acid secretion via an endocrine mechanism and was found to participate in intestinal fat-mediated inhibition of acid secretion. S-14 was selectively released after fat to plasma elevations that inhibited gastrin-stimulated acid secretion and this inhibitory effect by S-14 was reversed with a somatostatin antagonist. These inhibitory actions of S-14 on gastrin-stimulated gastric acid secretion and gastrin release were mediated through SSTR2. In conscious dogs, gastric acid regulates S-28 and S-14 after nutrient ingestion by separate mechanisms; muscarinic pathways differentially regulate S-28 and S-14 secretion and this effect is linked to the state of gastric acidity; and S-14, via activation of SSTR2, inhibits gastric acid secretion and gastrin release.Ph.D