Inhibition of secretin stimulated pancreatic secretion by pancreatic polypeptide.

The effect of PP on secretin-stimulated pancreatic secretion was assessed in five healthy subjects. During an intravenous infusion of BPP at a dose which produced plasma levels similar to those seen after meals in healthy young adults the volume and bicarbonate content of duodenal juice was reduced by 25% (p less than 0.05) and 24% (p less than 0.05) respectively, while protein and bilirubin concentrations were more markedly reduced by 68% (p less than 0.0005) and 67% (p less than 0.0005) respectively. PP, thus, may be an important inhibitory factor in the control of bilirubin and pancreatic enzyme secretion in man.     

Changes in gastric secretion after intracerebroventricular infusion of bombesin in dogs

Synthetic bombesin (BBS) was infused intracerebroventricularly in 14 mongrel dogs, to study the effects of the peptide on gastric secretion and on gastrin and neurotensin levels. The infusion was performed with a specific apparatus, and gastric fluid was collected with a Pavlov pouch. BBS was given in two series of experiments: as a bolus intracerebroventricular injection of 308.6 pmol/kg and as a continuous intracerebroventricular infusion at a rate of 617.3 pmol/kg/h for 30 min. The bolus injection caused a very significant decrease of gastric fluid volume, a significant decrease of HCl output, and a significant increase of its pH, while serum immunoreactive gastrin increased significantly. The continuous infusion of BBS caused similar changes in gastric secretion. The plasma neurotensin levels did not change. In conclusion, the intracerebroventricular administration of BBS increases the serum gastrin levels, decreases the volume and HCl content of gastric fluid, and increases its pH.     

Effect of circulating somatostatin on exocrine pancreatic secretion in conscious dogs

We determined the effects of exogenous somatostatin-14 (100 and 200 ng/kg/h; mimicking postprandial somatostatin concentrations) on pancreatic responses to a background infusion of secretion in combination with graded doses of CCK-8 in conscious dogs with chronic gastric and duodenal fistulas. The lower dose of somatostatin-14 (S-14), which produced S-14 plasma levels lower than measured after a meal, did not change basal or stimulated pancreatic secretion. The upper dose of S-14, which produced plasma S-14 concentrations slightly above the postprandial range, caused inhibition of pancreatic fluid and protein secretion to low doses of CCK-8 (p less than 0.05). The inhibition was surmountable with higher doses of CCK-8. We interpret these data as indicating that circulating S-14 is not an important hormonal regulator of exocrine pancreatic secretion.     

Intracolonic infusion of bile salt stimulates release of peptide YY and inhibits cholecystokinin-stimulated pancreatic exocrine secretion in conscious dogs

The purpose of this study was to examine the effect of transanal (intracolonic) infusion of bile acid on release of peptide YY (PYY) and cholecystokinin (CCK)-stimulated pancreatic exocrine secretion in seven conscious dogs. CCK-8 (50 ng/kg/h) was given intravenously for 120 min and either taurocholic acid (TA, 1 or 2 mmol/h) or saline was infused transanally (150 ml/h) during the 0-60-min period of CCK infusion. Transanal infusion of TA (1 or 2 mmol/h) significantly inhibited output of CCK-8-stimulated pancreatic protein, compared to transanal infusion of saline during the first 60 min. On the average, the magnitude of inhibition was approximately 45%. Plasma concentrations of PYY increased significantly in response to intracolonic infusion of TA or saline. Transanal infusion of TA (1 or 2 mmol/h) significantly increased plasma levels of PYY when compared with transanal infusion of saline during the first 60 min. The magnitude of the increase of plasma PYY levels was approximately 50 pg/ml (p less than 0.05). Plasma levels of pancreatic polypeptide were not altered significantly by transanal infusion of TA. Our results suggest that release of endogenous PYY by TA in the colon plays a role in the inhibition of CCK-stimulated pancreatic exocrine secretion. Bile salts in the hindgut may participate in the physiologic regulation of pancreatic exocrine secretion by stimulation of release of ilealcolonic PYY.     

Potentiation of lactation-induced oxytocin secretion by intracerebroventricular oxytocin in the conscious goat

The release of oxytocin into the cerebrospinal fluid (CSF) and plasma of lactating goats was studied following implantation of cisternal and lateral ventricular cannulae. Hand milking was associated with a significant increase in plasma concentrations of oxytocin, but no change in plasma concentrations of vasopressin or CSF concentrations of oxytocin. Intracerebroventricular (i.c.v.) infusion of oxytocin itself (1 pmol/min for 60 min) had no effect on basal plasma levels of oxytocin. It did, however, markedly potentiate the milking-induced increase in plasma oxytocin above the levels achieved during i.c.v. infusion of artificial CSF alone. In the goat, therefore, milking results in a selective release of oxytocin into the plasma, and this release can be potentiated by the presence of increased concentrations of oxytocin in the CSF.     

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 polypeptide and vagal stimulation of gastric and pancreatic secretion in dogs

In four dogs provided with pancreatic, gastric, and esophageal fistulae, the effects of bovine pancreatic polypeptide (BPP) infused at a physiological dose level (240 pmol per kg/hr) on gastric and pancreatic responses to sham-feeding were studied. The maximal gastric and pancreatic secretion was produced by pentagastrin and secretin, and OP-CCK infusion, respectively, with or without additions of BBP. Exogenous BPP did not change gastric acid and pepsin outputs stimulated by pentagastrin or sham-feeding, but significantly inhibited basal and maximally stimulated pancreatic protein secretion. The peak pancreatic protein, but not bicarbonate response to sham-feeding was reduced by about 31% by BPP. This reduction by BPP amounted to about 57% when the pancreas was stimulated maximally by OP-CCK. It is concluded the PP released by cephalic-vagal excitation does not affect gastric secretion, but inhibits pancreatic protein secretion, and thus might contribute to the lower pancreatic response to sham-feeding as compared with that produced by exogenous stimulants such as secretin and OP-CCK.     

Glucose turnover and insulin secretion in dogs with pancreatic allografts

Summary The endocrine function of pancreaticoduodenal allografts was studied in six dogs and compared with that of normal animals. The grafts were able to prevent the diabetic ketosis that was observed in a control group after total pancreatectomy without following transplantation. — Systemic hyperglycaemia enhanced the insulin release from the transplanted pancreas, as measured by increased IRI levels after intravenous glucose administration. In contrast, the stimulation of insulin secretion by oral glucose loading was less than in normal dogs, while the glucose assimilation was also increased in transplanted animals.-It was speculated that the duodenum might be more susceptible to immunological damage than the pancreas, and that consequently an impairment of the resorption of glucose and of the production of intestinal factors controlling the secretion of insulin may result.-In the near future, pancreatico-duodenal transplantation does not appears to become a therapeutical alternative to the conventional treatment of diabetes mellitus in man.     

Pancreatic polypeptide. Metabolism and effect on pancreatic secretion in dogs.

In dogs with gastric and pancreatic fistulas, porcine pancreatic polypeptide (PP) was infused intravenously in doses of 50, 100, 200, 400, and 800 pmol kg-1 hr-1 in the basal state and in doses of 100, 200, and 400 pmol kg-1 hr-1 during stimulation with submaximal doses of secretin (125 ng kg-1 hr-1) plus caerulein (50 ng kg-1 hr-1). Plasma concentrations of PP were measured by radioimmunoassay, and pancreatic bicarbonate and protein outputs were monitored. The half-time for disappearance of PP was 5.5 +/- 1.0 min, the metabolic clearance rate was 25.6 +/- 1.0 ml kg-1, and the volume of distribution was 209 +/- 42 ml kg-1. Basal pancreatic flow and protein output were significantly inhibited by the lowest dose of PP tested, 50 pmol kg-1 hr-1. The lowest dose of PP significantly inhibiting stimulated pancreatic secretion was 100 pmol kg-1 hr-1 for bicarbonate output and 200 pmol kg-1 hr-1 for protein output. The mean +/- SE peak increment in PP concentration in response to a meal of meat, 210 +/- 39 pM, was greater than the mean peak increment with the 400 pmol kg-1 hr-1 dose of exogenous PP, 175 +/- 19 PM. We conclude that exogenous doses of PP that produce smaller increments in PP concentration than those seen after feeding inhibit pancreatic bicarbonate and protein secretion stimulated by secretin and caerulein. This suggests that the amount of PP released by a meal is sufficient to inhibit pancreatic secretion.     

Inhibition of secretin release and pancreatic bicarbonate secretion by somatostatin infusion in man.

Five healthy students were investigated on two different days with or without a constant infusion of somatostatin (500 microgram/h) into an arm vein a fluoroscopically placed Lagerl?f tube was used for the collection of gastric and duodenal juice. After 30-min basal period, 40 ml 100 mmol/l HCl was infused into the midpart of the duodenum over 5 min through a thin catheter attached to the tube. Plasma immunoreactive secretin was measured by radioimmunoassay employing 125I-labelled synthetic secretin, antibody against synthetic secretin, and standards prepared from pure natural porcine secretin. Secretin levels without somatostatin infusion were 4.6+/-0.7 pmol/l (mean+/-S.E.M.) basally and rose to a peak of 21.8+/-6.2 pmol/l after duodenal acidification (p less than 0.05) and with somatostatin infusion were 4.4+/-0.4 pmol/l basally and rose to a peak of 6.7+/-1.7 pmol/l (n.s.) after duodenal acidification. Pancreatic bicarbonate output increased from 8.0+/-2.5 mumol/min (mean+/-S.E.M.) to 283+/-44 mumol/min without somatostatin infusion (p less than 0.05) and from 6.7+/-2.1 mumol/min to 70+/-13 mumol/min somatostatin (p less than 0.05). This study shows that somatostatin (500 microgram/h can inhibit the release of secretin and the pancreatic bicarbonate secretion after duodenal acidification in man.     

Pancreatic polypeptide release: role of stimulants of exocrine pancreatic secretion in dogs

There are apparent similarities in the mechanisms of the intestinal phase of exocrine and pancreatic polypeptide (PP) secretion by the pancreas. To characterize this relationship, we measured incremental responses of protein, bicarbonate, and PP to graded doses of intravenous secretin, caerulein, CCK8, CCK33, bethanechol, and intraduodenally perfused HCl, sodium oleate, and L-phenylalanine in dogs with gastric and pancreatic fistulas and compared them with average postprandial values. Secretin did not release PP at any dose studied, whereas intraduodenal HCl increased PP levels slightly at a load maximal for pancreatic secretion. Caerulein produced dose-related increases in PP secretion (maximal, 106% of meal response) but CCK8 and CCK33 had much less effect at doses equivalent for protein secretion. Bethanechol was a weak stimulant for PP only at the largest tolerable dose. L-Phenylalanine and sodium oleate markedly increased protein secretion, but only oleate clearly stimulated PP. Our results suggest a greater quantitative importance of the intestinal phase for exocrine than endocrine (PP) pancreatic secretion.     

Interactions between endogenous and exogenous insulin and human pancreatic polypeptide secretion

The relationships between exogenous and endogenous insulin and plasma human pancreatic polypeptide (hPP) were investigated. Three tests were performed in 8 healthy subjects: 1 degree--1 g tolbutamide was injected i.v. in 1 min., 2 degrees--50 ml 50% glucose solution and 7 U of Insulin were contemporaneously infused at constant rate for 60 min., 3 degrees--50 ml saline solution were infused as control. After the tolbutamide injection plasma glucose levels were unchanged between 0-10 min. At 5, 10, 15 min. an increase in C-Peptide (CPR) value and a significant decrease of hPP were observed. At 15, 30 and 45 min. plasma glucose was significantly lower than baseline and hPP levels strongly rose until the end of the test. The glucose-insulin infusion testing resulted in a rise in plasma glucose and CPR levels at 15 min. and a fall in plasma hPP at 30 min. The present findings suggest that in the first part of tolbutamide test, the endogenous insulin secretion, valued as CPR, seems to inhibit hPP release probably through a paracrine pathway.     

Effects of synthetic human gastrin-releasing peptide on pancreatic exocrine secretion and release of pancreatic polypeptide in conscious rats

The effects of a newly synthesized peptide, human gastrin-releasing peptide (hGRP), on the pancreatic exocrine secretion and the release of pancreatic polypeptide (PP) were examined in the conscious rat. Plasma PP concentrations were determined by a recently established specific radioimmunoassay for rat PP. Amounts of 0.18, 0.35, and 3.5 nmol/kg/h hGRP significantly stimulated both pancreatic exocrine secretion and 0.35 nmol/kg/h of hGRP increased PP release. Simultaneously infused proglumide (300 mg/kg/h) did not affect either pancreatic exocrine secretion or PP release. However, simultaneous infusion of atropine (100 micrograms/kg/h) slightly inhibited PP release, but did not restrict the incremental response of pancreatic protein secretion to hGRP. These results suggest that hGRP directly stimulates pancreatic exocrine secretion and PP release.     

Effect of rabbit anti-pancreatic polypeptide serum on postprandial pancreatic exocrine secretion in dogs

To determine whether pancreatic polypeptide (PP) is a physiologic inhibitor of pancreatic secretion, we have studied the effects of normal rabbit serum and anti-PP serum on pancreatic secretion during infusion of a physiologic dose of PP or intragastric food instillation in dogs. Infusion of 180 pmol/kg X h of PP, previously incubated with normal rabbit serum, induced increases in plasma PP (220 +/- 21 pmol/L) similar to those after the meal (213 +/- 51 pmol/L) and was accompanied by significant inhibition of pancreatic flow rate, bicarbonate output, and protein output (p less than 0.05) stimulated by secretin and cholecystokinin (n = 6). However, when the effect of exogenous PP was studied after in vivo administration of anti-PP serum or after previous in vitro incubation with anti-PP serum, no inhibition of pancreatic secretion was found, indicating that immunoneutralization of PP blocks the biologic activity of the hormone. Intragastric instillation of 400 ml of liver extract resulted in significant increases in pancreatic flow rate and outputs of protein and bicarbonate (p less than 0.01; n = 8), both during administration of normal rabbit serum and anti-PP serum. The postprandial increase in pancreatic secretion during administration of anti-PP serum was not significantly different from that during administration of normal rabbit serum. We, therefore, conclude that PP is not a physiologic inhibitor of postprandial pancreatic secretion.     

Effects of synthetic human gastrin-releasing peptide on pancreatic exocrine secretion and release of pancreatic polypeptide in conscious rats

The effects of a newly synthesized peptide, human gastrin-releasing peptide (hGRP), on the pancreatic exocrine secretion and the release of pancreatic polypeptide (PP) were examined in the conscious rat. Plasma PP concentrations were determined by a recently established specific radioimmunoassay for rat PP. Amounts of 0.18, 0.35, and 3.5 nmol/kg/h hGRP significantly stimulated both pancreatic exocrine secretion and 0.35 nmol/ kg/h of hGRP increased PP release. Simultaneously infused proglumide (300 mg/kg/h) did not affect either pancreatic exocrine secretion or PP release. However, simultaneous infusion of atropine (100 μg/kg/h) slightly inhibited PP release, but did not restrict the incremental response of pancreatic protein secretion to hGRP. These results suggest that hGRP directly stimulates pancreatic exocrine secretion and PP release.     

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 natural peptide YY on pancreatic secretion and cholecystokinin release in conscious dogs

The effects of natural peptide YY on pancreatic secretion under different stimulatory conditions and on fatty acid-induced cholecystokinin release were examined in five conscious dogs with pancreatic and gastric fistulas. Intravenous infusion of natural peptide YY at 1 and 0.2 g/kg/hr caused 60 and 40% inhibition of secretin- and cholecystokinin-stimulated secretion, respectively, and 40–50 and 20–40% inhibition of intraduodenal oleate stimulated secretion, respectively. A significant but transient decrease in the plasma cholecystokinin level was observed in response to peptide YY under oleate stimulation. The present study demonstrates that peptide YY has a potent inhibitory effect on both exogenously and endogenously stimulated pancreatic secretion and has a mild suppressive effect on fatty acid-induced cholecystokinin release, suggesting that this peptide is an important colonic inhibitor of pancreatic secretion.This work was supported in part by a grant from the Ministry of Education, Japan (A 59440057) and in part by NIH grant AM30415.     

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.A portion of this work has appeared in abstract form (Gastroenterology 82:1161, 1982) and was presented at the Annual Meeting of the American Gastroenterological Association, Chicago (Illinois), on May 18, 1982.     

Immunoneutralization of circulating pancreatic polypeptide and pancreatic secretion

To determine the role of endogenous pancreatic polypeptide (PP) as a physiological inhibitor of pancreatic secretion, normal rabbit serum (control) or rabbit PP-antiserum was administered intravenously to dogs with chronic esophageal, gastric, and pancreatic fistulas. In all dogs tested, sham-feeding and ordinary feed with a meat meal resulted in a marked rise in the plasma level of immunoreactive PP that coincided with an increase in the exocrine pancreatic secretion of HCO3- and protein. After intravenous administration of PP antiserum, endogenous plasma PP was almost completely bound by infused antibodies to PP, whereas no such binding was detected after infusion of normal rabbit serum. In contrast, plasma gastrin remained unchanged both under basal and stimulated conditions. Immunoneutralization of PP, released endogenously, failed significantly to affect gastric acid and pancreatic protein responses to sham-feeding and the pancreatic HCO3- and protein responses to feeding a meat meal in chronic pancreatic fistula dogs. However, the PP antiserum abolished, in part, the inhibitory effect of exogenous PP on pancreatic secretion stimulated by exogenous hormones. We conclude that endogenous PP is not a physiological inhibitor of exocrine pancreatic secretion, as has been suggested previously.