The cephalogastric phase of the pancreatic response to food in the dog

We studied post-meal pancreatic secretion and gastrin release in conscious dogs with duodenal Thomas cannulas. Normal dogs were tested in physiological conditions and with an i.v. infusion of atropine 20 micrograms/kg/h or secretin 0.5 CU/kg/h. The responses were also studied after antral and truncal vagotomy. In the early phase (0-20 min) of the response, before gastric emptying started, antral vagotomy reduced fluid and protein outputs, and truncal vagotomy reduced them still more. Atropine reduced only the protein response. Gastrin release reached a peak after 20-25 min. After antral and truncal vagotomy, gastrin release was reduced within 10 min after the meal. Late-phase (greater than 20 min) pancreatic secretion depended on the presence of chyme in the duodenum. The effects of atropine and antral vagotomy in the cephalogastric phase could be explained by antropancreatic reflexes stimulating fluid secretion (atropine-resistant pathway) and protein output (atropine-sensitive pathway).     

Gastric acid and pancreatic polypeptide responses to modified sham feeding. Effects of truncal and parietal cell vagotomy.

The effects of truncal vagotomy and parietal cell vagotomy on gastric acid secretion and plasma gastrin and pancreatic polypeptide release were studied in 28 duodenal ulcer patients under basal conditions and after modified sham feeding and infusion of pentagastrin (2 micrograms/kg/h). Before vagotomy gastric acid output in response to modified sham feeding was significantly higher than basal acid secretion in all subjects tested and reached about 45% of the pentagastrin maximum. No difference in the increase in acid response, or in the pancreatic polypeptide response to modified sham feeding was found between patients with high and low basal secretion. Plasma gastrin concentration was unaltered by modified sham feeding before and after truncal vagotomy or parietal cell vagotomy, although after vagotomy it tended to reach higher values than before this procedure. After truncal vagotomy, basal pancreatic polypeptide concentration was decreased and modified sham feeding-induced pancreatic polypeptide increment was completely eliminated. Four weeks after parietal cell vagotomy, the modified sham feeding-induced increment in plasma pancreatic polypeptide was significantly decreased and observed only in seven of 12 patients. Four to five years after parietal cell vagotomy all subjects responded to modified sham feeding with pancreatic polypeptide increment similar to that before vagotomy and in three of 12 patients acid response to modified sham feeding was seen. This study indicates that truncal vagotomy eliminates gastric acid and plasma pancreatic polypeptide responses to vagal excitation while parietal cell vagotomy abolishes gastric acid response and reduces temporarily the pancreatic polypeptide response to modified sham feeding (possibly because of transient impairment of the vagal innervation of the pancreas). (2) A high ratio of basal to maximal acid output in non-operated duodenal ulcer patients is not associated with a low acid response to modified sham feeding, nor with a high pancreatic polypeptide concentration, and (3) Restitution of the pancreatic polypeptide response to modified sham feeding five years after parietal cell vagotomy does not indication ineffective denervation of the parietal cells.     

The role of gastrointestinal peptides on pancreatic secretion in response to different stimulants in conscious rats

Summary Effects of intragastric food, intraduodenal amino acids, and intravenously administered bombesin and gastrin-releasing peptide (GRP) were examined in conscious rats with pancreatic fistula in terms of responses of exocrine pancreatic secretion, plasma levels gastrin, and cholecystokinin (CCK). Pancreatic juice and blood samples were collected at regular intervals before and after the stimuli. Intragastric food increased pancreatic secretion and plasma levels of gastrin and CCK. Intraduodenal infusion of amino acids had no effect on pancreatic secretion and plasma levels of gastrin and CCK. Intravenous infusion of bombesin at 1 μg/kg/h induced significant increases in pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Bombesin infusion at 10 μg/kg/h resulted in significant increases in pancreatic volume and protein outputs as well as plasma gastrin levels, but had no effect on plasma CCK levels. Intravenous infusion of GRP induced increases in pancreatic volume and protein outputs and plasma gastrin levels, but had no effect on CCK levels. Antrectomy resulted in significant decreases in basal levels of plasma gastrin. GRP-stimulated pancreatic volume and protein outputs were not significantly changed by antrectomy. In rats that underwent antrectomy, GRP infusion significantly increased pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Food-stimulated pancreatic secretion and plasma levels of gastrointestinal peptides of rats were similar to other species, but amino acids, bombesin, or GRP may not be the stimulants for CCK release in rats. The stimuli that release CCK from duodenal mucosa probably varies among species.     

Neural pathways for the release of gastrin,cholecystokinin, and pancreatic polypeptide after a meal in dogs

We have measured gastrin, cholecystokinin (CCK), and pancreatic polypeptide (PP) release after a meal in normal dogs under basal conditions and during atropine infusion, and after various neural sections. Denervation of the gastric antrum (antral vagotomy) abolished the early part of the gastrin response to food. Truncal vagotomy, celiac ganglionectomy, and atropine reduced the early release of CCK, which occurred before the start of gastric emptying, suggesting that a neural, cholinergic mechanism may release CCK immediately after a meal. PP release was abolished by truncal vagotomy, and also by antral vagotomy. As no direct pathways are known between the antrum and the pancreas, this suggests either that antral afferents are essential for this response or that vagally mediated hormone release from the antrum mediates PP release.     

Regulatory mechanism of bombesin on gastrin release

Bombesin has been demonstrated to stimulate gastrin release by an atropine-resistant mechanism. In the present study, the effects of truncal vagotomy and chemical sympathectomy on the gastrin release by exogenous and endogenous bombesin using rat antral mucosa in tissue culture were studied. Exogenous bombesin 10^-8 mol/l significantly stimulated gastrin release. The stimulation of gastrin release by bombesin was abolished by truncal vagotomy, but not altered by chemical sympathectomy. Bombesin antiserum inhibited gastrin release by blocking the effect of endogenous bombesin. The inhibition of gastrin release by bombesin antiserum was abolished by truncal vagotomy, but not altered by chemical sympathectomy. In addition, the concentrations of bombesin-like immunoreactivity in antral mucosa were not altered by truncal vagotomy. These results suggest that the mechanism of gastrin release by bombesin is influenced by non-cholinergic local nerves under vagal control.     

L-364,718, a new CCK antagonist,inhibits postprandial pancreatic secretion and PP release in dogs

The effects of L-364,718, a new CCK receptor antagonist, on food-stimulated exocrine pancreatic secretion and plasma levels of PP, insulin, CCK, and gastrin were examined in four conscious dogs with pancreatic fistulas. Intravenous injections of L-364,718 (20 nmol/kg) significantly inhibited pancreatic protein and enzyme responses by food (33% inhibition) but not juice volume output. Both rapid and secondary prolonged postprandial rises of plasma PP were also significantly suppressed by L-364,718 (50% inhibition); however, plasma levels of insulin were not altered. Postprandial levels of gastrin were not affected by L-364,718 administration, whereas 3-hr integrated CCK response was significantly enhanced by L-364,718. This study indicates that L-364,718 inhibits pancreatic protein and enzyme secretion and the release of pancreatic polypeptide stimulated by food in conscious dogs. This inhibition might be due to the selective blockage of receptor binding of circulating CCK molecules. The results suggest that L-364,718 may be useful for the physiological and pathophysiological studies associated with CCK.     

Effect of bombesin on extragastric gastrin in man

The effect of a protein test meal and a bombesin infusion on extragastric gastrin levels was studied in patients with truncal vagotomy, antrectomy, and gastroduodenostomy or gastrojejunostomy and in patients with total gastrectomy. In patients with vagotomy, antrectomy, and gastroduodenostomy and in patients with total gastrectomy the gastrin levels were raised by 33% and 35%, respectively, from basal after test meal, while during BBS infusion gastrin values decreased by 25% and 30%, respectively, from basal. In patients with vagotomy, antrectomy, and gastrojejunostomy, test meal and BBS infusion did not significantly alter basal gastrin values. It is concluded that BBS does not stimulate extragastric gastrin.     

Intracerebroventricular administration of cholecystokinin-8 elevates plasma pancreatic polypeptide levels in awake dogs

The effect of intracerebroventricular (ICV) administration of cholecystokinin-8 (CCK-8) (0.5, 1.0, 2.0, 4.0 micrograms) on plasma levels of pancreatic polypeptide (PP) was studied in conscious dogs. ICV administration of CCK-8 (1.0, 2.0, 4.0 micrograms) produced a rapid and transient elevation in plasma concentrations of PP. Peripheral muscarinic receptor blockade with atropine or truncal vagotomy abolished PP secretion induced by ICV CCK-8. Pretreatment with ICV atropine also prevented the elevation in plasma PP induced by CCK-8. Plasma levels of CCK-33/39, CCK-8, and gastrin were not affected by ICV CCK-8. Our results indicate that central administration of CCK-8 selectively elevated plasma PP concentration. Since the effect of CCK-8 on plasma PP was abolished by central and peripheral atropine pretreatment, as well as by vagotomy, central and peripheral vagal cholinergic mechanisms appear to participate in release of PP that is induced by CCK-8 given by ICV injection.     

Effects of an antral mucosectomy, L-364,718 and atropine on cephalic phase of gastric and pancreatic secretion in dogs

The purpose of this study was to determine the role of gastrin and cholecystokinin in the cephalic phase of gastrin release and gastric and pancreatic secretion in conscious dogs. Sham feeding in intact dogs increased gastric acid output to about 65% of histamine maximum and pancreatic protein to 23% of caerulein maximum. Significant increases in plasma gastrin and pancreatic polypeptide but not cholecystokinin occurred. Similar effects were obtained using insulin hypoglycemia or 2-deoxy-D-glucose glucocytopemia. Atropine eliminated gastric acid response to sham feeding, insulin, or 2-deoxy-D-glucose, significantly reduced the pancreatic protein response by about 60%, and abolished plasma pancreatic polypeptide but not plasma gastrin. Blocking of cholecystokinin receptors by L-364,715 did not affect gastric or pancreatic secretory responses to sham feeding, insulin, or 2-deoxy-D-glucose and failed to influence the accompanying increments in plasma gastrin and pancreatic polypeptide. In antral-mucosectomized dogs, sham feeding-induced acid output reached only 17% of histamine maximum but the increase in pancreatic protein output was similar to that in intact dogs. In these animals, background stimulation with G17I (62 pmol/kg per h) potentiated the gastric acid response to sham feeding but had little effect on pancreatic protein output. This study provides evidence that unlike gastric acid, the pancreatic protein response to physiological or pharmacological cephalic stimulation does not depend on vagally released gastrin but probably on direct vagal stimulation of the pancreas.     

Inhibition of insulin secretion by intracerebroventricular infusion of pancreatic polypeptide in conscious dogs

Previously, we demonstrated that peripheral infusion of pancreatic polypeptide (PP) inhibits insulin response to several stimuli through vagal innervation. Since PP is found not only in pancreas but also in brain or cerebrospinal fluid, we studied the effect of intracerebroventricular infusion of PP on insulin secretion before and after vagotomy in dogs. Mongrel dogs were settled with a chronic cannula allowing intraventricular infusions into the third (n = 4) or lateral (n = 4) cerebral ventricle. All the experiments were performed one week after the operation in a fully conscious, relaxed state. Porcine PP (pPP, 50 ng or 5 micrograms/dog in 100 microliter saline), which has the same primary structure with that of canine PP, or saline alone was infused into the cerebral ventricles for 5 minutes at the rate of 20 microliter/minutes. As stimuli of insulin secretion, modified sham feeding (MSF; sight and smell of food for 5 minutes), glucose injection (IV-Glucose; 0.5 g/kg/30 seconds, intravenously) and CCK-octapeptide infusion (IV-CCK-8; 0.07 micrograms/kg/5 minutes, intravenously) were applied immediately after (and in some experiments various intervals after) the end of pPP or saline infusion into the ventricles. Immunoreactive PP or insulin was measured by a specific radioimmunoassay. Administration of PP caused significant inhibition of insulin secretion by MSF, IV-Glucose and IV-CCK-8 without affecting basal insulin secretion. The observed effect of the peptide was most potent when infused into the third cerebral ventricle at a dose of 50 ng/dog and not in a dose-related fashion. The integrated insulin responses to MSF, IV-Glucose and IV-CCK-8 were 28, 58 and 30%, respectively, as those of controls. This effect was likely to be of central origin because an overflow of PP to the periphery could not be observed by PP radioimmunoassay. Prior transthoracic bilateral truncal vagotomy abolished the suppressive effect of PP on glucose- and CCK-8-induced insulin secretion. Furthermore, the time course study of CCK-8 suggested that PP could interact with the regions surrounding the third cerebral ventricle. These results suggest that PP affects the central nervous system to control pancreatic insulin secretion via the vagus nerve like other peptides/neuroregulators which modify physiological processes (e.g. insulin release, acid secretion, motility).     

Impaired pancreatic innervation after pyloric transsection in dogs. Reduced pancreatic polypeptide response to insulin hypoglycaemia

Pancreatic polypeptide (PP) is released by efferent vagal impulses and its secretion is impaired after truncal and selective gastric vagotomy while remaining unchanged after parietal cell vagotomy. In three dogs an innervated antral pouch with transsection of the pylorus was constructed. After this operation the PP response to insulin hypoglycaemia was significantly reduced as compared to the preoperative response. In another four dogs an innervated antral pouch was constructed without transsecting the pylorus. Postoperatively we found that the PP response to insulin hypoglycaemia was unchanged compared to preoperatively. These results seem to indicate that vagal fibres to the pancreas run in close anatomic relation to the pylorus, and their inevitable damage during pyloric transsection results in reduced endocrine pancreatic secretion to vagal stimuli.     

Effect of L-364,718 on GRP-stimulated pancreatic and gastric secretions and GI peptides in conscious dogs

The effect of L-364,718, a cholecystokinin (CCK) receptor antagonist, on exocrine pancreatic secretion, gastric secretion, and plasma levels of gastrointestinal (GI) peptides stimulated by gastrin-releasing peptide (GRP) was examined in five conscious dogs. Intravenous infusion of graded doses of synthetic porcine GRP (18, 36, and 178 pmol/kg/h) caused significant and dose-dependent increases in pancreatic and gastric juice secretion and in plasma levels of pancreatic polypeptide (PP), CCK, and gastrin. Intravenous injection of L-364,718 (20 nmol/kg) significantly inhibited GRP-stimulated pancreatic outputs of juice volume, protein, and amylase and plasma PP release. L-364,718, however, did not affect gastric juice volume and plasma levels of CCK and gastrin. The results suggest that endogenously released CCK is, at least in part, responsible for GRP-stimulated pancreatic protein and enzyme secretions and PP release in dogs. The results further suggest that GRP-stimulated pancreatic secretion might be, in part, a direct response of GRP to exocrine pancreas.     

Pancreatic polypeptide response to a meal before and after cutting the extrinsic nerves of the upper gastrointestinal tract and the pancreas in the dog

The role of the sympathetic and parasympathetic innervation in the release of pancreatic polypeptide (PP) basally and in response to a meal was studied after stepwise extrinsic denervation of the pancreas and the upper gastrointestinal tract in conscious dogs with gastric fistulae. One set of seven dogs was fed a meat meal (35 g/kg body weight) before and after truncal vagotomy and after truncal vagotomy plus celiac and superior mesenteric ganglionectomy, ie, extrinsic denervation of the pancreas and the upper gastrointestinal tract. In another set of six dogs, only ganglionectomy was performed. Experiments were repeated in the presence of atropine (50 g/kg body weight, given as an intravenous bolus 60 min prior to the meal). Truncal vagotomy significantly (P<0.05) reduced the postprandial 120-min integrated plasma PP response (IPPPR) by 84% as compared to the prevagotomy response. Before truncal vagotomy, atropine significantly reduced the IPPPR by 57%. After truncal vagotomy, atropine completely abolished the residual PP response. Additional celiac and superior mesenteric ganglionectomy did not alter the IPPPR already reduced by truncal vagotomy. With the vagus nerves intact, ganglionectomy alone had no effect on the IPPPR whether or not atropine was given. These findings indicate that (1) the splanchnic nerves do not play a significant role in postprandial PP release and (2) that the vagus nerves are important mediators of the response to a meal. The effect of atropine on postprandial PP release after truncal vagotomy may be due to interruption of short enteropancreatic reflexes, suppression of the intrinsic cholinergic activity of the pancreas, or inhibition of hormonally induced PP release.     

Role of cholecystokinin in bombesin- and meal-stimulated pancreatic polypeptide secretion in dogs

This study was undertaken to delineate the role of cholecystokinin (CCK) in bombesin- and meal-stimulated pancreatic polypeptide (PP) secretion in seven conscious dogs by studying: (1) the stimulatory effect of similar plasma levels of CCK induced by a meal and infusions of bombesin and the synthetic CCK analog cerulein on plasma PP, and (2) the inhibition of PP secretion by the CCK-receptor antagonist CR-1409 during these three stimuli. The stimulation of PP secretion during bombesin (11.0±1.6 nM/hr) and after the meal (8.9±2.0 nM/hr) were significantly (P<0.05) greater than during infusion of the CCK analog cerulein (2.7±0.4 nM/hr). CR-1409 significantly inhibited the bombesin- and meal-stimulated PP secretion to 2.0±0.4 nM/hr (81%; P<0.05) and 3.1±1.2 nM/hr (47%; P<0.05), respectively, while the cerulein-stimulated PP release was almost abolished to 0.2±0.1 nM/hr (93%; P<0.05) by the drug. These findings point to an important role for CCK in the regulation of bombesin- and meal-stimulated PP secretion.Supported by grant 13-37-43 from the Netherlands Foundation for Medical Research MEDIGON and grant Si 228/7-1 from the Deutsche Forschungsgemeinschaft.     

Pancreatic responses to endogenous and exogenous gastrin in the dog

Serum gastrin and pancreatic secretion were measured in conscious Thomas fistula dogs during infusion of increasing doses of porcine gastrin, against a background of secretin. Dose-response relationships were calculated for the effects of gastrin on pancreatic secretion. Gastrin release was also measured after a test meal and after vagal stimulation with 2-deoxyglucose. Peak serum gastrin levels after these stimuli were less than the serum gastrin level associated with the minimal effective dose of gastrin. From the dose-response relationship of serum gastrin and pancreatic protein output, it was possible to calculate the protein output corresponding to the peak gastrin levels after 2-deoxyglucose or a meal. These were equivalent to 20-30% of the observed protein response to these stimuli. We conclude that gastrin plays at most a small part in the stimulation of pancreatic secretion after a meal and in response to 2-deoxyglucose. We also found that truncal vagotomy reduces pancreatic sensitivity to gastrin.     

Effects of cholecystokinin and gastrin antagonists on pancreatic exocrine secretion stimulated by gastrin-releasing peptide.

The effects of a specific cholecystokinin (CCK) receptor antagonist (L364,718) and a gastrin receptor antagonist (L365,260) on gastrin-releasing peptide-10 (GRP-10)-stimulated pancreatic secretion were investigated in the anesthetized rat. GRP-10 stimulated pancreatic exocrine secretion in a dose-dependent manner. A dose of 1.0 nmol/kg/h elicited a significant increase in pancreatic protein output. L364,718 (2.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous CCK-8 (3.0 nmol/kg/h) on pancreatic secretion, did not suppress the excitatory effect of GRP-10. L365,260 (5.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous gastrin (20 micrograms/kg/h) on gastric acid secretion, did not suppress the excitatory effect of GRP-10 either. We concluded that CCK or gastrin do not mediate the excitatory mechanism of bombesin/GRP on pancreatic secretion. Since CCK and gastrin are the most probable candidates for excitatory mediator of bombesin/GRP, these results support the hypothesis that bombesin/GRP directly stimulates the exocrine pancreas in the rat.     

Gastric emptying and sieving of solid food and pancreatic and biliary secretions after solid meals in patients with nonresective ulcer surgery

This study was undertaken to compare with previously published findings in normal subjects and subjects after truncal vagotomy and antrectomy the effects of nonresective ulcer surgery on (a) gastric emptying, grinding, and sieving of solid food and on (b) pancreatic and biliary secretions. Six subjects with proximal gastric vagotomy and 7 subjects with truncal vagotomy with pyloroplasty were studied using a previously validated indicator perfusion system with its aspiration port placed in the proximal jejunum. All subjects were given a meal of 30 g of 99mTc-liver, 60 g of beefsteak, and 100 ml of H2O. In conjunction with a gamma-camera to measure total gastric emptying of 99mTc-liver, this method allowed us to estimate the fraction of 99mTc-liver emptied from the stomach as particles of less than 1-mm diameter; in addition, we were able to measure jejunal concentrations and outputs of bile salts and pancreatic enzymes. In subjects with proximal gastric vagotomy, all parameters studied were indistinguishable from normal. Subjects with truncal vagotomy and pyloroplasty behaved similarly to subjects with vagotomy and antrectomy, showing (a) early precipitous emptying of food, (b) heterogeneous distribution of half-emptying times, (c) near normal concentration of biliary and pancreatic secretions, (d) markedly reduced jejunal flow rates, and (e) a reduction in postcibal trypsin secretion. In contrast to subjects after truncal vagotomy and antrectomy, however, the majority of subjects with vagotomy and pyloroplasty did not show a persistent defect in grinding and sieving of solid food.     

Stimulation of gastrin release and gastric secretion: effect of bombesin and a nonapeptide in fistula dogs with and without fundic vagotomy.

Bombesin and a synthetic bombesin nonapeptide were studied by intravenous infusion at a dose of 0.5 microgram.kg-1.h-1 for 4 h in 7 dogs with esophagostomy and gastric fistula. In 3 of the dogs who had highly selective (fundic) vagotomy, mean integrated gastrin output over 4 h was double that in the 4 dogs with vagi intact during both nonapeptide (1,554 vs. 700 pg.ml-1.4 h-1) and bombesin infusion (2,442 vs. 1,440 pg.ml-1.4 h-1). Peak concentrations of serum gastrin reached during bombesin (490 +/- 100 vs. 320 +/- 90) were higher than those during nonapeptide infusion (270 +/- 40 vs. 160 +/- 28 pg/ml) in the vagotomized and intact dogs, respectively. The difference between vagotomized and vagally intact dogs suggests that the fundic vagotomy removed an inhibitor of gastrin release from the innervated antrum. Despite these differences in gastrin release, gastric acid output with the two peptides was the same (49--52 mEq/4 h) whether the fundus was denervated or innervated. This suggests that bombesin may stimulate gastric acid secretion by the release of an additional secretagogue which is not measured by the gastrin assay. Neither of the two inhibitors of gastrin release--antral acidification to pH 1.4 or less or atropine (100 microgram/kg)-- inhibited gastrin release by bombesin, even though the atropine reduced acid output by 80%. Bombesin is a potent gastric stimulus whose action is only partly explained by the measured gastrin release.     

Effects of amino acids on pancreatic polypeptide before and after vagotomy in the dog

Summary We have previously indicated a marked influence of the vagus nerve on postprandial pancreatic polypeptide secretion. The present study was designed to determine whether the vagus nerve also plays a role in the regulation of pancreatic polypeptide secretion by absorbed nutrients. The pancreatic polypeptide responses to 17 intravenously administered amino acids, as well as arginine and glucose, were measured and compared with those 1 year after truncal vagotomy in conscious dogs. In response to the infusion of a mixture of amino acids (20 g during 60 min), plasma pancreatic polypeptide concentrations decreased in normal dogs. The effect was, however, completely reversed by vagotomy, with a significant pancreatic polypeptide release being observed (p < 0.05). Arginine (5 g during 60 min) also showed a similar, although not statistically significant, effect. After intravenous bolus-injection of glucose (0.5 g/kg body weight), a transient decrease of pancreatic polypeptide secretion was found; vagotomy abolished this response. These results suggest that the vagus nerve may have a suppressive role in the process of pancreatic polypeptide secretion induced by intravenous amino acid(s) and glucose.