cholecystokinin and 4-diphenylacetoxy-1-1-dimethylpiperidinium

Although the molecular machinery and mechanism of cell secretion in acinar cells of the exocrine pancreas is well documented and clear, only recently has the pharmacophysiology of pancreatic exocrine secretion come to light. Therefore, we focus in this article on the current understanding of the pharmacophysiology of pancreatic exocrine secretion. The pancreatic secretory response to ingestion of a meal is mediated via a complex interplay of neural, humoral and paracrine mediators. A major role in the control of the intestinal phase of pancreatic secretion is attributed to vago-vagal enteropancreatic reflexes. In the scheme of this control mechanism, afferents originating in the duodenal mucosa, and efferents mediating central input on the pancreatic ganglia, activate intrapancreatic postganglionic neurons. Experiments utilizing specific receptor antagonists demonstrate the involvement of both muscarinic M1 and M3 receptors expressed in pancreatic acinar cells. Cholecystokinin (CCK), originally implicated in the humoral secretion of pancreatic enzymes, through a direct action on acinar CCK receptors, is also essential to the enteropancreatic reflex mechanism. CCK stimulation of the exocrine pancreatic secretion through excitation of sensory afferents of the enteropancreatic reflexes, is a paracrine mode of CCK action, and is probably the only one in humans and the predominant one in rats. In dogs, however, CCK acts on the pancreas via both the humoral and a paracrine route. More recent experiments suggest further possible sites of CCK action. Additionally, at the brain stem, vago-vagal enteropancreatic reflexes may be modulated by input from higher brain centres, particularly the hypothalamic-cholinergic system in the tonic stimulation of preganglionic neurons of the dorsal motor nucleus of the vagus projecting into the pancreas.

Topics: Animals; Cholecystokinin; Dogs; Guinea Pigs; Humans; Mice; Pancreas, Exocrine; Piperidines; Pirenzepine; Rats; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Cholecystokinin; Reflex; Vagus Nerve

Different routes of administration of CCK-33 and blockage of CCK-A and muscarinic (m3) receptors are used in this study to evaluate the mechanisms by which cholecystokinin can stimulate the exocrine pancreas.. The experiment was performed on eight anaesthetized pigs during control conditions and after administration of the CCK-A and m3 receptor antagonists, Tarazepide and 4-DAMP, respectively. Catheters were surgically implanted in the pancreatic duct for juice collection and in the gastric and right gastro-epipoic arteries and in the jugular vein, so that infusions of CCK-33 could be made exclusively to the duodenum/stomach, duodenum/pancreas or general circulation, respectively.. Infusion of a low dose of CCK-33 (13 pmol kg(-1)) to the general circulation did not affect pancreatic protein or trypsin output. When the same dose was given directly to the duodenum/stomach or the duodenum/pancreas, pancreatic output increased during both control conditions and after Tarazepide and/or 4-DAMP treatment, though the increase in trypsin output was lower after Tarazepide and/or 4-DAMP blockade. A high dose of CCK-33 (130 pmol kg(-1)) given peripherally stimulated the pancreatic secretion, but this response was totally abolished in Tarazepide and 4-Damp treated animals.. Pancreatic enzyme secretion due to CCK-33 stimulation depends on the presence of short duodenal-pancreatic peptidergic reflexes evoked mainly via low sensitive, probably CCK-B, receptors located in the duodenum/stomach. Pancreatic secretion evoked by peripheral CCK-33 in pharmacological doses was independent of m3 receptors blockade but depended on CCK-A receptors located elsewhere than in the duodenum/pancreas.

Topics: Animals; Benzodiazepines; Cholecystokinin; Duodenum; Muscarinic Antagonists; Pancreas; Pancreatic Juice; Piperidines; Receptor, Cholecystokinin A; Receptor, Muscarinic M3; Receptors, Cholecystokinin; Receptors, Muscarinic; Reflex; Swine; Trypsin

The purpose of this study was to determine the regulation of pancreatic polypeptide (PP) release by using pirenzepine (a specific M1 muscarinic receptor antagonist), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP, a specific M3 muscarinic receptor antagonist), atropine (a nonspecific muscarinic receptor antagonist), and loxiglumide (cholecystokinin, CCK, receptor antagonist) in dogs. In conscious dogs with chronic gastric and duodenal fistulas, release of PP and exocrine pancreatic secretion were stimulated by constant intravenous infusion of CCK-8 (200 ng/kg/h). Graded doses of pirenzepine (0.18-4.7 mmol/kg/h), 4-DAMP (6.7-180 nmol/kg/h), or atropine (0.89-24 nmol/kg/h) dose-dependently reduced plasma PP responses to CCK-8 without influence on exocrine pancreatic secretion. ID50 calculated from these results were 492 +/- 150 nmol/kg/h for pirenzepine, 10.7 +/- 1.8 nmol/kg/h for 4-DAMP and 19.4 +/- 5.2 nmol/kg/h for atropine. A similar sequence in the inhibitory potency was observed in 2-deoxy-D-glucose (2-DG, 100 mg/kg)-stimulated PP release, exocrine pancreatic, and gastric secretions. On the other hand, loxiglumide, a CCK receptor antagonist, did not influence PP release stimulated by 2-DG. These findings suggest that both CCK- and 2-DG-stimulated PP releases are mainly under cholinergic nerve control mediated by M3 muscarinic receptor in dogs.

Topics: Animals; Atropine; Cholecystokinin; Dogs; Female; Gastric Acid; Male; Pancreatic Juice; Pancreatic Polypeptide; Parasympatholytics; Piperidines; Pirenzepine; Proglumide; Receptors, Muscarinic; Vagus Nerve

The effects of hypothalamic microinfusions of cholecystokinin octapeptide and its antagonist L364,718 on cecocolonic myoelectrical activity were evaluated by electromyography in fasted and fed rats. The rats were chronically fitted with electrodes implanted on the cecum and proximal colon and cannulas placed bilaterally in either the ventromedial or lateral hypothalamus. In fasted rats, microinfusion of cholecystokinin octapeptide (10 ng/kg) into the ventromedial hypothalamus increased the spike-burst frequency of the cecum and the colon by 45.6% and 43.7%, respectively, during the 30-minute period after treatment. The injection of cholecystokinin octapeptide (10 ng/kg) into the lateral hypothalamus had no effect on either cecal or colonic motility. Feeding increased the frequency of cecal and colonic spike bursts by 52.1% and 50.1% for 30 minutes postprandially. When infused bilaterally into the ventromedial hypothalamus 10 minutes before feeding, L364,718 (1 or 5 micrograms/kg) abolished the increase of the frequency of cecal and colonic contractions induced by the meal. Infused into the lateral hypothalamus at similar dosages, L364,718 had no effect on the postprandial enhancement of cecocolonic motility. Increase of cecocolonic spike-burst frequency induced by feeding or by cholecystokinin octapeptide injected into the ventromedial hypothalamus was abolished by previous intracerebroventricular but not intraperitoneal administration of atropine (1 microgram) and 4-diphenylacetoxy-N-methylpiperidine (1 microgram), a selective muscarinic M2-receptor antagonist. In contrast, pirenzepine (1 microgram, intracerebroventricularly) did not significantly reduce the meal- or cholecystokin octapeptide-induced increase in cecal and colonic motility. These results suggest that, in rats, (a) cholecystokinin octapeptide is involved in the generation of the cecocolonic motor response to a meal and these effects are mediated through cholecystokinin octapeptide receptors located in the ventromedial hypothalamic nuclei, and (b) these postprandial colonic motor changes involve central cholinergic activation through muscarinic M2 receptors.

Topics: Animals; Atropine; Benzodiazepinones; Cholecystokinin; Colon; Devazepide; Electromyography; Food; Gastrointestinal Motility; Hypothalamic Area, Lateral; Hypothalamus; Male; Parasympatholytics; Piperidines; Pirenzepine; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Receptors, Muscarinic; Sincalide; Ventromedial Hypothalamic Nucleus