gastrin-releasing-peptide and 4-diphenylacetoxy-1-1-dimethylpiperidinium

Gastrin-releasing peptide (GRP) stimulates insulin secretion by a direct islet effect. In this study, we initially demonstrated, by immunocytochemistry of the mouse pancreas, GRP immunoreactive nerve fibers within exocrine tissue, islets, and intrapancreatic ganglia. A more pronounced GRP innervation was found in ganglia compared with in islets. We therefore studied whether indirect cholinergic mechanisms contribute to the insulinotropic action of GRP. In mice, the insulinotropic response to GRP (4.25 nmol/kg i.v.) was inhibited by the m3-selective, muscarinic receptor antagonist 4-diphenylacetoxy-N-methyl piperidine methobromide (4-DAMP, 0.21 mol/kg; by 68%, P < 0.05) and by the ganglionic blocker hexamethonium (28 mol/kg; by 98%, P < 0.05). In contrast, in isolated islets, 4-DAMP or hexamethonium (10 or 100 microM) did not inhibit GRP (100 nM)-induced insulin secretion. Furthermore, afferent denervation by neonatal capsaicin did not affect the insulin response to GRP. We conclude that the insulinotropic effect of GRP in the mouse is mediated by both direct islet effects and through activation, at the ganglionic level, of postganglionic cholinergic nerves. In vivo, the indirect cholinergic mechanism predominates.

Topics: Animals; Blood Glucose; Capsaicin; Cells, Cultured; Female; Ganglia, Sympathetic; Gastrin-Releasing Peptide; Glucagon; Hexamethonium; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred Strains; Muscarinic Antagonists; Pancreas; Piperidines; Receptor, Muscarinic M3; Receptors, Muscarinic

Studies were made of pancreastatin (PST) secretion from a human PST-producing cell line (QGP-1N) in response to various secretagogues. Cells with immunoreactivity for PST were observed in monolayer cultures of QGP-1N cells. Carbachol stimulated PST secretion and the intracellular Ca2+ mobilization concentration dependently in the range of 10(-6)-10(-4) M. The PST secretion and Ca2+ mobilization induced by carbachol were inhibited by atropine. The calcium ionophore (A23187) stimulated PST secretion. However, cholecystokinin and gastrin-releasing peptide did not stimulate either PST secretion or Ca2+ mobilization. Secretin also did not stimulate PST secretion. The glucose concentration in the culture medium had no effect on PST secretion. These results suggest that PST secretion is mainly regulated by acetylcholine through a muscarinic receptor, and that an increase in intracellular Ca2+ plays an important role in stimulus-secretion coupling in QGP-1N cells.

Topics: Acetylcholine; Adenoma, Islet Cell; Atropine; Calcimycin; Calcium; Carbachol; Chromogranin A; Gastrin-Releasing Peptide; Humans; Pancreatic Hormones; Pancreatic Neoplasms; Parasympatholytics; Peptides; Piperidines; Pirenzepine; Receptors, Muscarinic; Sincalide; Tumor Cells, Cultured