The Effect of Gastrin-Releasing Peptide on Porcine Pancreaticobiliary Bicarbonate Secretion Is mediated by secretin

Glad H, Svendsen P, Ainsworth MA, Olsen O, Rehfeld JF, Schaffalitzky de Muckadell OB. The effect of gastrin-releasing peptide on porcine pancreaticobiliary bicarbonate secretion is mediated by secretin. Scand J Gastroenterol 1994;29:195-202.

The effect of gastrin-releasing peptide (GRP) (250, 500, 1000pmol/kg-h) on the pancreaticobiliary bicarbonate secretion, the pancreatic protein secretion, and the plasma concentrations of secretin and cholecystokinin (CCK) was studied in the anaesthetized pig. Infusion of GRP (1000 pmol/kg-h) increased the portal plasma concentrations of secretin from 0.9 to 13.6pmol/l and CCK from 1.2 to 38.4pmol/l, the pancreatic bicarbonate secretion from 0.01 to 5.6mmol/h, the hepatic bicarbonate secretion from 0.5 to 4.1mmol/h, and the pancreatic protein secretion from 3 to 680mg/h. Blocking of CCK-A receptors by MK-329 did not significantly change the effect of GRP, whereas prevention of secretin release by removal of the small intestine caused a 13-fold reduction in the GRP-induced pancreatic bicarbonate secretion and completely abolished the effect on hepatic bicarbonate secretion but did not change the effect on pancreatic protein secretion. We conclude that the effect of GRP on pancreaticobiliary bicarbonate secretion is not mediated through the release of CCK but more likely through the release of secretin and that the effect on pancreatic protein secretion is possibly a direct effect of GRP.     

Subtypes of muscarinic receptors in canine pancreatic secretion in vivo and in vitro

In conscious dogs with esophageal, gastric and pancreatic fistulae, sham-feeding and meat feeding increased the pancreatic protein secretion to a peak, reaching about 39% and 69% of CCK8 maximum, and raised plasma pancreatic polypeptide (PP) levels. Pirenzepine given intravenously (i.v.) (30 nmol.kg-1 or 3 mumol.kg-1) reduced dose-dependently the pancreatic protein and plasma PP responses to sham-feeding and meat feeding, being about 100 times less potent as an inhibitor than atropine. Neither pirenzepine nor atropine affected near-maximal pancreatic bicarbonate and protein responses to secretin (164 pmol.kg-1.h-1) and CCK8 (170 pmol.kg-1.h-1), but both antimuscarinic agents significantly inhibited pancreatic responses to lower doses of these secretagogues. When added to the incubation medium of dispersed canine pancreatic acini, pirenzepine reduced dose-dependently the amylase responses only to urecholine, and not to CCK or gastrin, being about 1000 times less potent as an inhibitor than atropine. This report provides an evidence that pirenzepine inhibits pancreatic secretion in a similar manner to atropine, but that pirenzepine, in both in vivo and in vitro studies, is 2-3 orders of magnitude less potent as an inhibitor than atropine, indicating that the muscarinic pathway of the exocrine pancreas has a low affinity for pirenzepine and may thus involve M2-receptors.     

Postprandial Pancreatic Secretion and Plasma Hormones in Dogs with Pancreatic Fistula

The responses of exocrine pancreas, plasma secretin, and gastrin to a test meal were studied in six dogs prepared with gastric and duodenal fistulas. The experiment was doubly repeated in each dog. Pancreatic juice was diverted to the exterior by direct cannulation into the major pancreatic duct. Volume, bicarbonate, and protein secretion of pancreatic juice were rapidly increased and then gradually reduced after the ingestion of the meal. Plasma secretin concentration reached a peak at 25 min after the ingestion of the meal and remained higher than the basal level for about 3 h. Plasma gastrin concentration rapidly reached a higher plateau which lasted for 40 min after the load of the test meal. A close correlation was observed between bicarbonate secretion and the increment in plasma secretin concentration and between protein secretion and the increment in plasma gastrin concentration. When pancreatic juice is diverted to the exterior, endogenously released secretin and gastrin appear to play an important role in postprandial pancreatic secretion.     

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.     

Role of secretin and CCK in the stimulation of pancreatic secretion in conscious dogs. Effects of atropine and somatostatin

The role of gut hormones, such as secretin and CCK, in the stimulation of pancreatic secretion by duodenal HCl or oleate and by meat feeding has been studied in conscious dogs before and after pretreatment with atropine and somatostatin. Plasma hormones were measured by specific and sensitive radioimmunoassays. Duodenal perfusion with HCl and oleate stimulated dose-dependently pancreatic HCO3 and protein secretion and raised plasma levels of secretin and CCK, respectively. Atropine reduced significantly both HCO3 and protein secretion but did not affect plasma secretin and CCK levels in these studies. Both exocrine pancreatic secretion and plasma secretin and CCK levels were suppressed by somatostatin. Meat feeding caused a marked pancreatic HCO3 and protein secretion accompanied by a significant increase in plasma secretin and CCK which seem to play an important role in the postprandial pancreatic stimulation. Both atropine and somatostatin reduced the pancreatic secretion induced by exogenous hormones but only somatostatin, but not atropine, significantly decreased plasma secretin and CCK responses to intestinal stimulants. We conclude that both atropine and somatostatin reduce the pancreatic responses to duodenal HCl or oleate or to meat feeding but only somatostatin is capable of suppressing the release of secretin and CCK.     

Effects of secretin antibody on gastric acid inhibition and pancreatic bicarbonate stimulation by acidified liver extract meal in dogs

Duodenal acidification is known to inhibit gastric H+ secretion while stimulating pancreatic HCO-3 secretion, but the mechanisms of these effects have not been fully explained. This study was designed to determine the role of endogenous and exogenous secretin in gastric inhibition and pancreatic stimulation by an acidified liver extract (LE) meal in conscious dogs prepared with chronic gastric and pancreatic fistulas pretreated with normal serum (control) or anti-secretin serum. In control tests, plasma gastrin and gastric H+ secretion showed a marked rise with LE meals at pH ranging from 7.0 to 4.0, but significantly declined at pH 3.0 and 2.0. Plasma secretin and pancreatic secretion started to rise with LE meals at pHs below 4.5, and both reached peaks at pH 2.0. Exogenous secretin infused at graded doses suppressed plasma gastrin and gastric H+ responses to LE meals at doses of 1.0 and 2.0 U/kg-h, but increased, dose-dependently, plasma secretin and pancreatic HCO-3 starting with a dose of 0.03 U/kg-h. Following the administration of anti-secretin serum, the effects of exogenous secretin on plasma gastrin and secretin levels as well as on gastric and pancreatic secretion were almost completely abolished. The increase in plasma secretin and pancreatic HCO-3 responses to LE meals at pH below 4.5 were also abolished by anti-secretin serum, but the suppression of plasma gastrin level and the inhibition of gastric H+ responses to LE meals at lower pH (3.0 and 2.0) remained virtually unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a liquid meal given as a bolus into the jejunum on human pancreatic secretion

Major features of pancreatic secretion stimulated by a meal depend on intestinal phase mechanisms. However, an intrajejunal (i.j.) meal infusion is widely used for the treatment of inflammatory pancreatic diseases when the resting of the gland is desired. This study was undertaken to compare the effects of an intragastric (i.g.) and an i.j. complete fluid (Lundh) test meal on pancreatic enzyme secretion. Eight men (mean age, 43 years; range, 31-48) free from pancreatic disease were studied. Pancreatic secretion was measured via a multiple-lumen tube by aspiration of the duodenal juice. After a fasting period, the Lundh test meal was placed in the stomach or the upper jejunum. After the i.g. administration of the test meal, the aspirated duodenal juice was reinfused into the jejunum. The effect of atropine infusion (0.5 microg/kg/h) on the pancreatic enzyme secretion was studied. The pancreatic amylase, trypsin, and lipase outputs were determined. The plasma levels of cholecystokinin (CCK) and of gastrin were measured by bioassay and radioimmunoassay, respectively. The trypsin, amylase, and lipase secretions increased significantly after either an i.g. or an i.j. test meal intake. The trypsin, amylase, and lipase outputs were significantly decreased during the i.j. perfusion as compared with i.g. administration. The gastrin levels increased significantly after i.g., but remained unchanged after i.j. administration. The CCK release attained its maximum 40 and 60 min after the i.g. and i.j. test meal, respectively. However, the CCK release was significantly lower during the i.j. administration as compared with i.g. perfusion. An atropine infusion significantly reduced the i.g. and i.j. test meal-stimulated enzyme outputs. An i.j.-administered meal stimulates the pancreatic enzyme secretion, but this effect is significantly lower than that which occurs on i.g. administration. The i.j. meal-stimulated secretion of pancreatic enzymes is subject to both cholinergic and peptidergic regulation. The deficiency of gastrin and the delayed and decreased CCK release are believed to account for the reduced enzyme output.     

A physiological role for cholecystokinin as a regulator of gastrin secretion.

To explore the role of cholecystokinin (CCK) in regulating gastrin secretion in humans, the effect of a CCK antagonist (loxiglumide) on meal-stimulated hormone responses was investigated. Subjects received 500 mL of a liquid test meal in the presence and absence of loxiglumide (22 mumol.kg-1.h-1). In the control experiments, both plasma gastrin and CCK levels increased postprandially. In loxiglumide-treated subjects there was a marked elevation in gastrin (area under the curve, 11,042 +/- 1493/120 min vs. 2156 +/- 281 pg/120 min) and CCK levels compared with the control experiment. These observations were confirmed in experiments with modified sham feeding and gastrin-releasing peptide stimulation in which loxiglumide pretreatment also caused a significant increase in gastrin release compared with saline (P less than 0.05). Further studies with intravenous infusion of gastrin, CCK-8, and CCK-33 with and without loxiglumide showed that the increases in CCK and gastrin during loxiglumide application cannot be explained by alterations in clearance rates. The findings of this study show that postprandial gastrin secretion is influenced by CCK and support the concept of a negative feedback control of gastrin secretion by CCK.     

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.     

Neurotensin and the exocrine pancreas

It has been postulated that neurotensin (NT) has a physiological role in the regulation of the exocrine pancreas, but this is controversial. Using the Thomas cannula canine model, the effect of intravenous NT, in physiological and pharmacological doses on exocrine pancreatic secretion, and on plasma pancreatic polypeptide, secretin and cholecystokinin (CCK) levels is reported. The infusion of physiological doses of NT alone (0.2 pmol/kg per min) did not stimulate pancreatic secretion; however, in conjunction with secretin, NT stimulated protein and bicarbonate output, the latter synergistically. Higher doses of NT (20 and 100 pmol/kg per min) resulted in a dose-dependent stimulation of pancreatic volume, bicarbonate and protein secretion. Cholinergic blockade with atropine reduced pancreatic secretion stimulated by low doses of NT (2–20 pmol/kg per min), but at higher doses (100 pmol/kg per min) protein secretion was reduced whilst bicarbonate secretion was enhanced. The infusion of graded doses of NT had no effect on plasma secretin or CCK levels. In contrast, NT did release pancreatic polypeptide in a dose-dependent manner, but only at pharmacological infusion levels. NT, acting synergistically with other hormones, may thus play a role in exocrine pancreatic stimulation.     

Atropine abolishes the potentiation effect of secretin and cholecystokinin-octapeptide on exocrine pancreatic secretion in humans

Potentiating action between secretin and cholecystokinin on exocrine pancreatic secretion of bicarbonate has been well recognized. In the present study, we studied the effect of atropine on potentiating action on pancreatic exocrine secretion stimulated by exogenous secretin in physiologic dose and cholecystokinin-octapeptide in humans. Using a dye-dilution technique and a duodenal triple-lumen tube, pancreatic secretion of both bicarbonate and trypsin was determined while gastric juice was completely aspirated. Secretin given i.v. in a dose of 2.7 pmol/kg/h, which was known to achieve a similar plasma concentration of secretin after meal in humans, and cholecystokinin-octapeptide 26.2 pmol/kg/h potentiated pancreatic secretion of bicarbonate but not the pancreatic trypsin output. Atropine given i.v. in a dose of 1 mg/h abolished the potentiation effect of the two hormones on pancreatic bicarbonate output. Since the inhibitory effect of atropine on the secretin-stimulated bicarbonate output was statistically significant, the major inhibitory effect of atropine on the potentiation of pancreatic bicarbonate secretion appears to be its effect on the action of secretin.     

Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans.

Pancreatic enzyme secretion is regulated in humans by the cholinergic system and by cholecystokinin (CCK). The interaction between both regulatory systems in response to exogenous and endogenous stimulation was analyzed in the present study using the cholinergic antagonist atropine and the CCK antagonist loxiglumide. A dose-dependent stimulation of pancreatic enzyme output was achieved either by duodenal perfusion of graded caloric loads or by IV infusion of increasing doses of cerulein. Prestimulated pancreatic secretion was inhibited by atropine and loxiglumide. Atropine furthermore almost completely blocked meal-stimulated pancreatic secretion, whereas loxiglumide caused 60% inhibition. The enzyme response to graded doses of exogenous CCK was significantly inhibited by atropine and loxiglumide. Plasma levels of CCK were not altered by atropine but increased with infusion of loxiglumide. This study supports the concept that pancreatic enzyme secretion is predominantly dependent on a cholinergic tone and that CCK modulates the enzyme-secretory response.     

Plasma CCK levels in patients with pancreatic insufficiency

After stimulation with a Lundh test meal, plasma concentrations of cholecystokinin (CCK) and pancreatic polypeptide (PP) and output of pancreatic enzymes were measured in 33 patients with exocrine pancreatic insufficiency and 26 healthy subjects. Patients with impairment of pancreatic function were subdivided into those with moderate and severe insufficiency. Plasma CCK and PP were measured by radioimmunoassay. Fasting plasma CCK in patients with pancreatic insufficiency (5.8±1.1 pmol/liter) did not differ significantly from controls (4.2±0.6 pmol/liter). After endogenous stimulation with a Lundh meal, plasma CCK increased in both groups without significant differences over 2 hr. Basal and stimulated plasma levels of pancreatic polypeptide (PP) were markedly decreased only in patients with severe pancreatic insufficiency. Our results demonstrate that basal and meal-stimulated CCK levels in patients with pancreatic insufficiency do not differ from controls. Furthermore the extent of functional impairment of the exocrine pancreas did not influence basal and postprandial CCK release.     

The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion

Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.     

Eradication of Helicobacter pylori restores the inhibitory effect of cholecystokinin on postprandial gastrin release in duodenal ulcer patients.

Helicobacter pylori infection may be associated with duodenal ulcer (DU) and accompanied by enhanced gastrin release but the mechanism of this H pylori related hypergastrinaemia in DU patients is unclear. Cholecystokinin (CCK) has been implicated in the feedback control of gastrin release and gastric acid secretion in healthy subjects. This study therefore investigated if CCK participates in the impairment of postprandial gastrin release and gastric secretion in six DU patients. Tests were undertaken with and without elimination of endogenous CCK by loxiglumide, a selective CCK-A receptors antagonist, before and after eradication of H pylori with triple therapy (omeprazole, amoxicyllin, bismuth). In H pylori positive DU patients, the post-prandial decline in pH (with median pH 3.5) was accompanied by a pronounced increment in plasma gastrin but the administration of loxiglumide did not affect significantly this postprandial rise in plasma gastrin and gastric pH profile. After eradication of H pylori, the plasma gastrin concentration was reduced while the median postprandial pH was significantly increased (median pH 4.3). The administration of loxiglumide resulted in significantly greater increase in postprandial plasma gastrin and greater decrease in pH (median pH 3.1) in these patients. This study shows that (a) infection with H pylori is accompanied by an enhanced gastrin release and gastric acidity in DU patients, (b) the failure of loxiglumide to affect plasma gastrin or gastric acid secretion in H pylori infected DU patients could be attributed, at least in part, to the failure of endogenous CCK to control gastrin release and gastric secretion by releasing somatostatin, and (c) the test with loxiglumide may be useful in the identification of patients with impaired feedback control of gastrin release and gastric secretion resulting from infection with H pylori.     

Effect of atropine on intestinal phase of pancreatic secretion in man

The effect of atropine on prestimulatory and Lundh-meal-stimulated pancreatic secretion and on plasma cholecystokinin (CCK) levels has been studied in 20 human volunteers. Prestimulatory secretion was lowered by infusion of atropine. From 10 to 30 min after ingestion of the Lundh meal, atropine had no effect on secretion. From 30 to 120 min, the stimulated enzyme secretion was reduced by 90% during infusion of atropine. Plasma CCK levels were not altered by atropine. Similar results were obtained when the test meal was instilled into the duodenum to exclude a delay of gastric emptying caused by atropine. These data show that cholinergic blockade does not interfere with CCK-mediated stimulation of pancreatic secretion during the first 30 min after ingestion of a meal, and that afterwards the intestinal phase is mainly under cholinergic control.     

Cholecystokinin in the control of gastric acid secretion in man.

This study was designed to determine the role of cholecystokinin in the control gastric acid secretion in men using loxiglumide, a specific cholecystokinin receptor blocker. Three groups of healthy subjects (A, B, and C) were used; group A--for studies with postprandial gastric secretion, group B--for studies with exogenous gastric secretagogues and group C--for 12 hour intragastric pH-metry. Cephalic phase stimulated by modified sham feeding in group A subjects increased gastric acid secretion to about 50% of pentagastrin maximum and the treatment with loxiglumide in a standard dose (20 mumol/kg iv loading dose plus infusion of 20 mumol/kg/h afterwards) failed to affect this secretion. Gastric acid response to a 5% peptone meal instilled intragastrically greatly enhanced gastric acid secretion and plasma gastrin concentration but the addition of loxiglumide in the standard dose resulted in further increase in both gastric acid and plasma gastrin responses to peptone meal. Infusion of caerulein in gradually increasing doses (15-120 pmol/kg/h) and gastrin releasing peptide (25-200 pmol/kg/h) resulted in a dose dependent stimulation of gastric acid secretion reaching about 35% and 25% of maximum attained with pentagastrin. When loxiglumide was added in a standard dose, the acid responses to caerulein and gastrin releasing peptide were further increased two to three fold attaining the peak reaching, respectively, about 100% and 50% of pentagastrin maximum. In group C subjects, 12 hour pH-metry revealed the usual increase in gastric pH after each meal in tests with placebo. Loxiglumide (1200 mg tablets tid, po) resulted in significantly lower pH after each meal and this was accompanied by significantly higher gastrin responses than in placebo tests. We conclude that cholecystokinin released by peptone meal, ordinary meals or gastrin releasing peptide exerts a potent inhibitory influence on gastric acid secretion and gastrin release in men and this inhibition involves subtype A cholecystokinin receptors.     

Volume and enzyme kinetics of human pancreatic secretion after endogenous stimulation with the Lundh test meal

The present study was undertaken to investigate the volume and enzyme kinetics of human pancreatic secretion, after endogenous stimulation with a Lundh test meal, and evaluate the most reliable enzyme and collection period. The prestimulatory volume rates did not differentiate normal from pathologic pancreatic function. After ingestion of the test meal, the immediate increase in volume secretion was identical in healthy subjects and patients with pancreatic insufficiency. The latter showed a drastic reduction of prestimulatory and postprandial enzyme secretion. Cimetidine taken orally 12 and 2 h before the test meal study had no effect on volume and enzyme secretion and endogenous CCK release. Especially in severe pancreatic insufficiency, this modification simplified the performance of the Lundh test. The estimation of lipase and trypsin gave a significant correlation between Lundh test and secretin-cerulein test. The endogenous stimulation by Lundh test meal is a reliable test for routine diagnostic and scientific purposes.     

Effect of loxiglumide, a cholecystokinin antagonist, on pancreatic polypeptide release in humans

The purpose of this study was to determine the role of cholecystokinin in the regulation of postprandial pancreatic polypeptide secretion in humans. The pancreatic polypeptide responses to modified sham feeding and gastric instillation of a test meal were first compared with the response to oral ingestion of the same meal. The experiments were repeated under cholinergic (atropine) and cholecystokinin (loxiglumide) blockade. Atropine completely abolished the pancreatic polypeptide response to sham feeding and caused significant reductions after gastric and oral food intake. Loxiglumide, on the other hand, significantly reduced pancreatic polypeptide release to oral food (51% inhibition) without affecting the response to sham feeding. In separate experiments using a duodenal perfusion system, the effects of atropine and loxiglumide on intestinal phase-stimulated pancreatic polypeptide release were examined, and both cholinergic and cholecystokinin blockade induced complete suppression. It was concluded (a) that cholecystokinin is involved in postprandial pancreatic polypeptide response, especially during the intestinal phase stimulation, and (b) that the cholinergic system is crucial and superimposed on cholecystokinin in stimulating pancreatic polypeptide release.