Atropine suppression of basal and metoclopramide-induced human pancreatic polypeptide secretion in man.

The administration of metoclopramide (MET) increased human pancreatic polypeptide (hPP) levels in 17 of 18 male and female control subjects. In all the control subjects, the increase was from a mean (+/- SD) basal level of 96 +/- 60 pg/ml, to a peak of 221 +/- 170 pg/ml. The peak occurred at 30 min, and levels had decreased by 60 min in all subjects. Atropine pretreatment in five male control subjects significantly decreased basal hPP levels and completely abolished the response to MET. It thus likely that the hPP increase consequent to MET administration is related to the latter's cholinergic properties.     

The influence of somatostatin on glucagon and pancreatic polypeptide secretion in the isolated perfused human pancreas

Summary The current study was undertaken to determine whether intraislet somatostatin regulates glucagon or pancreatic polypeptide (PP) secretion in the human pancreas. A high-affinity, high-specificity monoclonal somatostatin antibody (CURE.S6) was used to immunoneutralize somatostatin in the isolated, perfused human pancreas. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs media with either 3.9 or 12.9 mM glucose. Sequential test periods separated by basal periods were performed with infusion of either exogenous somatostatin-14 (SS-14), CURE.S6, or a combined infusion. Infusion of SS-14 did not significantly alter glucagon or PP secretion during low-glucose or high-glucose perfusion. Immunoneutralization of intraislet somatostatin with CURE.S6 resulted in a significant increase of glucagon secretion under low-glucose conditions (ΔX=15±3 pM) (p<0.05), but did not significantly effect glucagon secretion under high-glucose conditions (ΔX=−2±3 pM) (p=NS). PP secretion remained unchanged during CURE.S6 infusion. Combined infusion of SS-14 and CURE.S6 did not significantly alter glucagon or PP secretion. The data suggest that intraislet somatostatin may have an inhibitory role in the regulation of glucagon secretion during low-glucose conditions and that intraislet somatostatin does not regulate PP secretion in the isolated, perfused human pancreas.     

The influence of aging on basal and secretin stimulated pancreatic exocrine secretion in the unanesthetized rat

We explored the effect of aging on basal and secretin stimulated pancreatic exocrine secretion because of clinical reports of pancreatic exocrine insufficiency in aging individuals. We studied conscious rats, 3, 4, 13, 24 and 27 months of age, with external drainage of pancreatic secretions, unobstructed bile flow, and complete diversion of gastric secretions. Pancreatic juice was measured for volume, and assayed for bicarbonate, protein content, and amylase activity. Aged animals (27 months of age) had drastic reductions in both basal and stimulated secretory volume, bicarbonate output, protein output, and amylase output. Thus, aging in this animal model is associated with marked decrease in exocrine pancreatic secretions, suggesting that the isolated case reports in man may represent a more common problem than has been appreciated.     

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.     

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.     

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.     

Adrenergic modulation of pancreatic polypeptide secretion

In order to examine the effect of adrenergic influences on pancreatic polypeptide (PP) secretion, a series of insulin tolerance tests was carried out in five normal volunteers. Control ITT's, as well as ITT's following pretreatment with oral cyproheptadine (4 mg q 6 hr for 48 hr ITT-cyp), and intravenous phentolamine (5 mg stat, then 0.5 mg/min for 120 min, ITT-phe), and propranolol (3 mg stat, then 0.08 mg/min for 120 min, ITT-pro), were performed. Alpha blockade established during ITT-phe augmented the peak PP concentration after insulin from 1470 ± 472 to 2684 ± 840 pg/ml (p < 0.05) and resulted in an increase in net response of 57 ± 4.7% (p < 0.001) as assessed by areas under the curves. In contrast, beta adrenergic blockade during ITT-pro suppressed the PP peak down to 696 ± 218 pg/ml, or 49% of control (p < 0.01), and diminished the net response by 43% (p < 0.01), despite the prolongation of hypoglycemic values observed during ITT-pro. Pretreatment with cyproheptadine did not alter the PP response to ITT. When propranolol was infused without ITT, PP concentrations more than doubled from 89.6 ± 4.1 pg/ml to values ranging from 175 ± 36.2 to 213 ± 42.4 pg/ml at 30–120 min (p < 0.05). Phentolamine infusion alone did not influence PP. Alpha adrenergic blockade augments, and beta blockade suppresses, the PP response to insulin hypoglycemia. The mechanism of the rise in PP following propranolol infusion alone may be secretory agonism of the drug, a parasympathetic response to it, or an influence on PP clearance.     

Effect of bovine pancreatic polypeptide on basal pancreatic and biliary outputs in man

Basal pancreatic and biliary outputs were examined in seven healthy volunteers during intravenous infusion of bovine pancreatic polypeptide (BPP) at a mean dose of 320 pmoll kg/hr. BPP significantly (P<0.02) inhibited outputs of trypsin and bilirubin, without affecting bicarbonate. These studies suggest the possibility that pancreatic polypeptide may have a role in the regulation of biliary and pancreatic enzyme secretion in man.A preliminary report of this work has been published as an abstract (1).     

The effect of pancreatic polypeptide and peptide YY on pancreatic blood flow and pancreatic exocrine secretion in the anesthetized dog

Pancreatic polypeptide (PP) and peptide YY (PYY) are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests intermediate mechanisms of action. To examine the role of pancreatic blood flow in these inhibitory effects, xenon-133 gas clearance was used to measure pancreatic blood flow while simultaneously measuring pancreatic exocrine secretion. PP or PYY (400 pmol/kg/h) was administered during the intermediate hour of a 3-h secretin (125 ng/kg/h)/cholecystokinin octapeptide (CCK-8) (50 ng/kg/h) infusion. Exocrine secretion and pancreatic blood flow during the PP or PYY hours were compared with that observed in the first and third hours of the secretin/CCK-8 infusion. PP and PYY significantly inhibited secretin/CCK-8-induced pancreatic exocrine secretion. In addition, PYY (but not PP) significantly reduced pancreatic blood flow during secretin/CCK-8 stimulation. Nevertheless, there was no correlation between pancreatic blood flow and bicarbonate or protein outputs. It is concluded that changes in pancreatic blood flow do not mediate the inhibitory effects of PP or PYY on the exocrine pancreas.     

Effects of rat pancreatic polypeptide on islet-cell secretion in the perfused rat pancreas.

Pancreatic polypeptide (PP) secretory cells are abundant in the islets of Langerhans. Results concerning the effects of exogenous PP on islet-cell secretion are controversial. This might be due in part to species specificity, given that most reports refer to studies performed using PP of bovine, porcine, or human origin in a heterologous animal model. Thus, we have investigated the influence of synthetic rat PP (80 nmol/L) on unstimulated insulin, glucagon, and somatostatin release, and on the responses of these hormones to glucose (11 mmol/L) and to arginine (3.5 mmol/L) in a homologous animal model, the perfused rat pancreas. Infusion of rat PP (rPP) reduced unstimulated insulin release by 35% (P = .03), and the insulin responses to glucose by 65% (P = .029) and to arginine by 50% (P = .026), without modifying glucagon output. rPP did not affect somatostatin secretion, either in unstimulated conditions or in the presence of 11 mmol/L glucose. However, it induced a clear-cut increase in somatostatin release during 3.5 mmol/L arginine infusion. Our observation that rPP inhibited insulin secretion without affecting glucagon and somatostatin output points to a direct effect of PP on B-cell function. However, during aminogenic priming of the D cell, the inhibition of insulin output induced by rPP was accompanied by an increase in somatostatin release. Thus, in this circumstance, it might be considered that the blocking effect of PP on B-cell secretion could be, at least in part, mediated by a D-cell paracrine effect.     

The effect of physical stress on gastric secretion and pancreatic polypeptide levels in man

Twelve healthy subjects were exposed to a 4-day period of hard physical exercise, calorie supply deficiency, and severe sleep deprivation. The basal acid output (BAO), the sham-feeding-induced acid output (MAOsh), and the pentagastrin-stimulated acid output (MAOpg) were measured immediately after this stress period and in a control experiment performed several weeks later. The stress induced a threefold increase in the median BAO and an increase (p less than 0.05) in the MAOsh, which, however, was not significantly elevated when basal-subtracted. MAOpg was unchanged. In contrast to acid, pepsin output was not influenced by stress. The human pancreatic polypeptide (hPP) level in serum increased twofold after the stress. The integrated hPP response induced by modified sham feeding was higher (p = 0.02) after the stress than in the control experiment. The results show that physical stress has separate influence on the gastric secretion of acid and pepsin.     

Effect of somatostatin on basal and stimulated pancreatic secretion in the rat

The effect of linear somatostatin on pancreatic exocrine secretion in anaesthetized rats has been studied. Basal secretion of amylase was significantly inhibited by an infusion of 100 microgram/100 g/h somatostatin, but increased fourfold after a bolus injection of 50 microgram/100 g. CCK-stimulated enzyme and volume secretion were inhibited by somatostatin. Somatostatin did not influence secretin-stimulated bicarbonate concentration or rate of secretion in the dose range in which enzyme secretion was inhibited.     

Feedback regulation of basal pancreatic secretion in humans

The effect of intrajejunal infusion of pancreatic juice on basal pancreatic secretion was studied in patients who had received pancreatoduodenectomy for pancreatic, biliary, or duodenal malignancy. Pure pancreatic juice was obtained through a drainage tube inserted into the main pancreatic duct. There was little fibrosis in the pancreatic remnant and daily pancreatic juice output was more than 200 ml. After intraluminal infusion of pancreatic juice, water, protein, bicarbonate, and enzyme outputs were decreased significantly by about 30%. Intraluminal trypsin also reduced pancreatic secretion. Trypsin inhibitor (aprotinin) suppressed the significant decrease caused by autopancreatic juice or trypsin solution. We conclude that basal pancreatic secretion in humans is under negative feedback control by intestinal pancreatic juice or tryptic activity.     

Proglumide stimulates basal pancreatic secretion in the conscious rat

The effect of proglumide, a glutaramic acid derivative, on pancreatic secretion was examined in vivo in the conscious rat with and without the return of bile-pancreatic juice (BPJ) to the intestine. Intravenous infusion of both 300 and 60 mg/kg proglumide significantly decreased protein output in a dose-related manner during BPJ diversion, but did not completely abolish the pancreatic hypersecretory response to BPJ diversion. Conversely, during basal secretion with BPJ being returned to the intestine, 300 mg/kg/h of proglumide increased the protein output. Dibutyryl cyclic GMP infused simultaneously with proglumide did not abolish the stimulatory effect of proglumide on basal secretion. It was concluded that proglumide inhibits pancreatic protein output during stimulated secretion by means of the luminal feedback mechanism but increases protein output during basal (BPJ returned) secretion in the conscious rat.     

Pancreatic polypeptide secretion in patients with chronic pancreatitis and after pancreatic surgery.

AIM: We investigated polypeptide (PP) secretion under basal conditions, in response to bombesin infusion and to meal ingestion in patients with chronic pancreatitis (CP) and patients after different types of pancreatic surgery. METHODS: Included were patients with CP without (n = 20) and with (n = 30) exocrine pancreatic insufficiency, patients after duodenum preserving resection of the head of the pancreas (DPRHP; n = 20), after Whipple's procedure (n = 19), following distal pancreatectomy (DP; n = 12), and healthy controls (n = 36). RESULTS: In CP patients basal and bombesin stimulated PP levels were significantly (p<0.01) reduced compared to controls only when exocrine insufficiency was present. Meal-stimulated PP secretion was significantly (p<0.01-0.05) reduced in CP patients both with and without exocrine insufficiency. Plasma PP peak increments after bombesin and meal ingestion correlated significantly with exocrine function. Basal PP, meal, and bombesin-stimulated PP secretion had low sensitivities of 22%, 42%, and 60% respectively, in detecting chronic pancreatitis. In patients after pancreatic surgery that included pancreatic head resection (DPRHP or Whipple operation) basal and stimulated PP secretion were significantly (p<0.01-0.05) reduced. CONCLUSION: Basal and meal or bombesin-stimulated PP levels are significantly reduced in patients with CP only when exocrine insufficiency is present. Determination of plasma PP levels has low sensitivity and is not useful in detecting chronic pancreatitis without exocrine insufficiency. In patients after pancreatic surgery, PP secretion is dependent on the type of operation (head vs tail resection).     

Exocrine pancreatic enzyme and calcium secretion in health and pancreatitis.

Calcium, enzyme, and total protein secretion were measured in secretin stimulated pancreatic juice in health, "early" chronic pancreatitis, and in chronic calcific pancreatitis. Increased concentrations of trypsin, total protein, and calcium, and increased outputs of calcium and protein were shown to be present in the "early" stages of the disease, indicating that an environment conducive to the formation of protein plugs and possibly later calcification already exists.     

Effects of a gastric partitioning operation for morbid obesity on the secretion of gastric inhibitory polypeptide and pancreatic polypeptide

Nine morbidly obese subjects were studied with a test meal before and 3 months after a gastric partitioning operation. After the operation the postprandial release of plasma gastric inhibitory polypeptide was significantly increased, the plasma pancreatic polypeptide release was similar, and the serum insulin release significantly reduced as compared with the preoperative values.     

Inhibition of rat basal pancreatic secretion by intraduodenal bile

The effect on basal exocrine pancreatic secretion of diversion from and reintroduction into the duodenum of bile has been studied on conscious rats provided with pancreatic, biliary and duodenal fistulae. Diversion of bile from the intestine augmented protein output by 30%. After an eight-hour diversion recirculation of bile into the duodenum reduced pancreatic protein output by 30%; volume being not significantly modified. When either bile was diverted or the main bile duct was ligated, a similar inhibition of protein secretion was observed after intraduodenal injections of 20 mM solutions of taurocholate, taurochenodeoxycholate, chenodeoxycholate, and cholate, and of synthetic mixed micelles (bile salts, lecithin). Inhibitory action of bile salts on pancreatic secretion was seen equally whether or not the bile salts were in free or conjugated form or pancreatic juice returned to the intestine. We conclude that unlike man and the dog, bile as well as pancreatic juice inhibits the basal pancreatic exocrine secretion of the rat.