Inhibition Of Pancreatic Secretion Research Articles

Beta-Adrenergic Inhibition of Pancreatic Secretion in Dogs

Terbutaline, a beta-adrenergic agonist, administered subcutaneously inhibits pancreatic exocrine secretion. We studied the effects of intravenous terbutaline and propranolol on cholecystokinin-stimulated pancreatic secretion in conscious dogs. Terbutaline inhibited pancreatic juice volume, bicarbonate concentration, bicarbonate output and protein output, but had no effect on protein concentration. Propranolol blocked this inhibition and had no effect on the response to cholecystokinin. These observations suggest that (1) terbutaline inhibits pancreatic secretion by a beta-adrenergic mechanism and (2) the primary effect of terbutaline on canine exocrine pancreas is inhibition of water and bicarbonate secretion.

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 · 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 < 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 < 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.

Characteristics of Inhibition of Pancreatic Secretion by the β-Adrenergic Agonist, Terbutaline

This study was performed to characterize the inhibitory effects of terbutaline on pancreatic secretion. In experiments with pancreatic fistula dogs, intravenously administered terbutaline significantly reduced pancreatic juice volume, bicarbonate concentration, bicarbonate output, and protein output evoked by secretin or the octapeptide of cholecystokinin but had no effect on protein concentration. Subcutaneously administered terbutaline significantly reduced meal-stimulated pancreatic juice volume, bicarbonate concentration, bicarbonate output, and protein output and increased protein concentration in a dose-related manner. In other experiments, terbutaline had no effect on amylase release from dispersed guinea pig pancreatic acini. These observations suggest that the primary effect of terbutaline on the in vivo exocrine pancreas is inhibition of water and bicarbonate secretion; reduced output of pancreatic protein may be secondary to decreased flow of pancreatic juice.

Three-day continuous drainage of pancreatic juice in the cortisone-treated conscious rat: analysis of enzyme activities and ultrastructural changes.

We have investigated the short-term effects of hydrocortisone (60 mg/kg per day) and placebo on basal and stimulated pancreatic secretion in the conscious rat. Volume and enzyme secretion were determined; fine structural changes were examined simultaneously. The pancreatic and bile ducts were cannulated separately; pancreatic juice was drained via an isolated fistula, and bile was recirculated into the duodenum. The application of hydrocortisone led to an almost complete inhibition of the secretory response of the exocrine pancreas when stimulated with 0.25 U secretin in combination with 5 X 10(-8) g caerulein per h. It strongly affected the secretion rates of volume, protein, lipase, chymotrypsin, trypsin and carboxypeptidase, whereas the secretion rate of alpha-amylase continued to show a slight increase after stimulation. After stimulation with secretin and caerulein, the hydrocortisone-treated animals showed a higher density of zymogen granules in the acinar cell and an increase in the number of autophagic vacuoles in comparison to the equally stimulated placebo-treated rats. It is concluded that the short-term inhibition of pancreatic secretion by hydrocortisone occurs largely as a result of an inhibition of cellular enzyme discharge.

The direct inhibition of pancreatic electrolyte secretion by noradrenaline in the isolated perfused cat pancreas.

The continuous infusion of noradrenaline into the arterial supply of the isolated saline-perfused pancreas caused a dose-dependent rise in perfusion pressure, a reduction in perfusion rate and an inhibition of pancreatic secretion. With increasing dose there was always a greater reduction in secretion rate than there was of perfusate flow rate. Manual reduction of the perfusion rate resulted in a reduction in secretion rate. When noradrenaline reduced the perfusate flow by 44.2 +/- 6.0% the secretion rate fell by 76.6 +/- 14.1%. Manual reduction of the perfusion flow rate by a similar amount (43.0 +/- 5.7%) only reduced the secretion rate by 41.4 +/- 7.0%. The infusion of noradrenaline, when all calcium had been removed from the perfusate, caused only a small increase in perfusion pressure with little change in the perfusion flow whilst at the same time the inhibition of electrolyte secretion was relatively unaffected. The vasomotor and secretory effects of noradrenaline were abolished by phentolamine. It is concluded that noradrenaline inhibits pancreatic electrolyte secretion by a direct action on the secretory cell and indirectly by vasoconstriction and that both these effects are mediated through the alpha-receptor.

Effect of partial exclusion of pancreatic juice on rat basal pancreatic secretion

Experiments were conducted to determine the relationship between the percentage of pancreatic secretion diverted from the intestine and pancreatic exocrine secretion in conscious rats. Rats with cannulas draining bile and pancreatic juice had increasing percentages (0%–100%) of their pancreatic secretion diverted from the intestine while all bile was returned. Stimulation of pancreatic protein and fluid output by diversion of pancreatic juice from the intestine did not occur if 10% of the volume of pancreatic juice secreted was returned to the intestine. Return of 5% of pancreatic secretion reduced the pancreatic protein response by half (compared with complete diversion). The results are interpreted as evidence for a threshold in negative feedback regulation by luminal proteases whereby increased pancreatic secretion does not occur until luminal protease activity is reduced by >90%. The results also suggest that inhibition of pancreatic secretion by proteases in pancreatic juice is far more effective than inhibition by proteases (e.g., trypsin) infused singly.

Cholinergic stimulation and inhibition of pancreatic secretion in alcohol-adapted dogs.

There is indirect evidence of increased release of acetylcholine in the exocrine pancreas of chronically alcoholic dogs. Our aim was to ascertain whether altered pancreatic responsiveness to cholinergic stimulation was an associated phenomenon. Pancreatic dose-response tests with graded bethanechol stimulation on constant secretion stimulation, without or with a low dose of background atropine, were performed in four chronic gastric and duodenal fistula dogs after 3 and 12 months of intragastric feeding with ethanol. The secretory protein response was dose-dependently increased by bethanechol in the control dogs but not in the test dogs, after 3 or 12 months of daily alcohol. They responded significantly only to a dose four to eight times greater than the minimum effective dose in the control dogs. Atropine depressed the entire dose-response curve of these dogs but only the response to the greatest doses in the alcohol-treated dogs. In previous experiments caerulein and/or secretin evoked increased secretory responses of bicarbonate in chronically alcoholic dogs, but this was not the case in this study with bethanechol, which did not have a stimulating effect on bicarbonate in either test or control dogs. Concomitant atropine, however, unmasked a bicarbonate-stimulating effect of bethanechol in control but not in treated dogs. It is concluded that chronic alcohol-feeding, already after 3 months, leads to a diminished pancreatic responsiveness to cholinergic stimulation and inhibition of protein output, as evidenced by at least a fourfold increase of the minimum effective dose of bethanechol and diminished inhibitory action of atropine.

Inhibition of pancreatic exocrine secretion and augmentation of the release of gut glucagon-like immunoreactive materials by intraileal administration of bile in the dog.

The effect of intraileal instillation of bile, a stimulant of gut glucagon-like immunoreactive materials (gut GLI), on secretin-stimulated pancreatic secretion was examined in anesthetized dogs. Intraileal bile significantly inhibited the flow rate of secretin-stimulated pancreatic secretion. The inhibition of pancreatic secretion was accompanied by an elevation of plasma concentration of gut GLI. Taking the inhibitory effect of glucagon on pancreatic exocrine secretion into consideration, it could be reasonably postulated that gut GLI may be a mediator of bile-induced ileal inhibition of pancreatic exocrine function.

Influence of secretin on the course of acute experimental pancreatitis in rats.

Inhibition of pancreatic secretion is a widely accepted therapeutical principle of acute pancreatitis. However, stimulation of water and bicarbonate secretion may be beneficial by washing out the ductular system in pancreatitis. Secretin (2 and 16 CU/kg body weight) or saline were given to rats at different time intervals after induction of sodium taurocholate pancreatitis. Pancreatic necrosis and edema were slightly more marked after secretin but secretin had no influence on the survival time and rate or enzymatic parameters. It is concluded that in the rat secretin-induced pancreatic secretion does not alter the course of acute pancreatitis.

Effect of human pancreatic polypeptide and its C-terminal hexapeptide on pancreatic secretion in man and in the dog.

Human pancreatic polypeptide (HPP) and its C-terminal hexapeptide (HP-PP) were infused intravenously in graded doses into healthy human subjects and dogs with chronic pancreatic fistula during submaximal stimulation with secretin. Plasma levels of PP were measured by radioimmunoassay, and pancreatic volume flow and bicarbonate and protein outputs were monitored. PP and HP-PP in humans did not affect secretion-induced volume flow or bicarbonate secretion, but at the highest doses it reduced the protein outputs. In dogs both HPP and HP-PP inhibited dose-dependently the pancreatic volume flow and bicarbonate and protein outputs. There was a linear correlation between the dose of HPP infused and the increments in plasma PP levels in these experiments. The inhibition of pancreatic secretion occurred at doses of exogenous HPP which produced blood plasma PP concentrations not significantly different from those normally seen after a meat meal. We conclude that there is a marked difference in the effect of HPP on the exocrine pancreas in man and the dog, that PP may play a role as a physiological inhibitor of pancreatic protein secretion in man and of both bicarbonate and protein secretion in the dog, and that the effect of HPP on the exocrine pancreas can be mimicked by its C-terminal hexapeptide.

Meal stimulated gastrin and pancreatic polypeptide levels before and after partial gastric transection for morbid obesity.

The aim of the study was to determine the basal and meal stimulated plasma gastrin and pancreatic polypeptide levels in six morbidly obese patients before and after partial gastric transection (gastroplasty), an operation which results in the distention of the stomach with a small volume of food. The partial gastric transection involved the creation of a proximal gastric pouch of approximately 100 ml, with a 1.2 cm diameter lumen between the proximal and distal gastric pouch. Basal gastrin and pancreatic polypeptide were not altered by the operation. The magnitude of the pancreatic polypeptide response to the mean was significantly depressed, although the time course was not changed. Inhibition of pancreatic secretion is thought to be a physiological function of pancreatic polypeptide, hence its decreased release warrants further investigation in relation to the effect of partial gastric transection on pancreatic function.

Pancreotone, an inhibitor of pancreatic secretion in extracts of ileal and colonic mucosa.

1. Pancreotone is a polypeptide material obtained from ileal and colonic mucosa by extraction with alcohol and subsequent precipitation by bile salts. 2. In anaesthetized cats in inhibits the actions of secretin on the pancreas, and of pancreozymin on the pancreas and gall-bladder. 3. Pancreotone has a less powerful inhibitory action on pentagastrin-stimulated gastric secretion. 4. The actions of pancreotone resemble the inhibitory effects on the pancreas and stomach of intraileal and intracolonic infusions of oleic acid and other substances in cats with the vagal and splanchnic nerves cut. Pancreotone may be the humoral mediator of these inhibitory effects. 5. A possible relationship between the actions of pancreotone and somatostatin on the stomach, and of pancreotone and pancreatic polypeptide on the pancreas, is discussed.

PANCREATIC ASCITES AND PLEURAL EFFUSIONS

Two cases of pancreatic ascites are presented and reviewed, together with 92 cases of internal pancreatic fistula reported in the recent literature. Alcohol abuse is the predominant aetiological factor, and chronic pancreatitis with an associated pseudocyst the most common pathological finding. The diagnosis depends on clinical suspicion and can be confirmed by the estimation of amylase and protein levels in the aspirated fluid. Medical treatment includes the aspiration of fluid accumulations, inhibition of pancreatic secretion, and nutritional augmentation. The use of pancreatography is recommended as a guide to the appropriate surgical procedure in patients who do not respond to medical therapy. Overall results indicate a cure rate of 77% and a mortality of 19%.

Inhibition of pancreatic secretion by enkephalin and morphine in dogs

The nature and extent of enkephalin- and morphine-induced inhibition of pancreatic bicarbonate and protein secretion were studied in dogs with chronic pancreatic fistulae after administering exogenous secretin or octapeptide of cholecystokinin and stimulants for the endogenous release of these hormones. Enkephalin and morphine competitively inhibited the pancreatic bicarbonate secretion induced either by exogenous secretin or duodenal acidification. This inhibition was partially reversed by naloxone, an opiate antagonist. Opiate substances also profoundly inhibited pancreatic protein response to octapeptide of cholecystokinin and to various stimulants of endogenous cholecystokinin release. We conclude that enkephalin and morphine strongly inhibit the pancreatic responses to exogenous and endogenous stimulants by a mechanism involving separate opiate receptors.

Effect of motilin on pancreatic secretion.

Motilin and secretin were compared in regard to their effects on pancreatic bicarbonate and protein secretion in conscious dogs provided with chronic pancreatic fistulas. Dose-response analysis showed that maximal bicarbonate response to motilin was about 5% of that to secretin and maximal protein response was about 35% of that to caerulein. The interaction of these two peptides showed that motilin is a potent inhibitor of secretin-induced bicarbonate secretion. Since motilin is released by duodenal alkalinization and inhibits pancreatic bicarbonate secretion, it is possible that this peptide is involved in the feedback mechanism of inhibition of pancreatic secretion by alkaline pancreatic juice present in the duodenum.

Action of Intragastric Ethanol on the Pancreatic Secretion of Conscious Rats

A surgical procedure has been disigned which permits injection in the stomach and the duodenum by separate catheters, collection of the pancreatic juice during the experiments, recirculation of the pancreatic juice into the duodenum between experiments, and a normal circulation of bile in rats. Experiments were performed in conscious rats given either 20% ethanol or water. In rats submitted to daily ethanol consumption for 13 months, the intragastric injection of 2 g/kg 20% ethanol considerably increased the pancreatic secretion of protein and, to a lesser extent, of water. In control non-alcoholic rats, a short period of increased secretion is followed by a major inhibition of pancreatic secretion, this reverse reaction to ethanol of pancreatic secretion according to whether or not rats are adapted to regular ethanol consumption is similar to what has been previously observed in dog. In chronic alcoholic rats, the release of secretin is probably not very different from controls.

Direct and Indirect Effects of Nicotine on Rabbit Pancreatic Secretion

The mechanism of nicotine-induced inhibition of pancreatic exocrine secretion of water and bicarbonate was studied, using in vitro and in vivo preparations of rabbit pancreas. High concentrations of nicotine (10 mM) in the bathing fluid of the in vitro pancreas caused decreases in flow rate, bicarbonate secretion, and tissue ATP content. In anesthetized rabbits, doses of nicotine, comparable to those absorbed by human smokers, inhibited flow and bicarbonate secretion but had no effect on tissue ATP content. Norepinephrine and epinephrine mimicked the pancreatic effects of nicotine in vivo. Phenoxybenzamine stimulated secretion of water and bicarbonate in vivo and blocked the inhibitory effects of nicotine and catecholamines. These results indicate that inhibition of pancreatic secretion by nicotine is probably mediated by release of catecholamines.

Characteristics of inhibition of pancreatic secretion by glucagon.

The inhibition of cholecystokinin (CCK)-induced pancreatic secretion by glucagon was studied in four dogs with chronic pancreatic fistulas and open gastric fistulas. After establishing a constant level of secretion by intravenous infusion of CCK at a constant rate (doses: 3, 6, 12 and 24 U/kg/h) glucagon was given by constant intravenous infusion for 1 h in constant doses (6, 12, 25 and 50 μg/kg/h). From the dose response curves to CCK alone and CCK plus 25 μ/kg/h glucagon, the Michaelis-Menten analysis was typical of competitive inhibition, i.e., the calculated maximal response was similar and the dose required for half maximal response was different. Glucagon also inhibited pancreatic secretion elicited by intraduodenal instillation of a solution of L-tryptophan and L -leucine. It was concluded that glucagon inhibits the CCK-stimulated pancreatic secretion in the dog and that this inhibition is competitive.

Inhibition of pancreatic secretion in man by cigarette smoking.

Cigarette smoking has been linked to an elevated incidence of duodenal ulcer disease in smokers, although the mechanism is unclear. In 23 young normal subjects single or double secretin tests were performed during non-smoking and smoking periods. Cigarette smoking inhibited the secretion of pancreatic juice and bicarbonate in light smokers (< one pack/day for < three years). Heavy smokers (> one pack/day for > three years) exhibited depressed pancreatic secretory rates during non-smoking periods. Inhibition of pancreatic alkaline secretion by cigarette smoking could be the link between the habit and duodenal ulcer disease.

Mechanisms of Nicotine-Induced Inhibition of Pancreatic Secretion of Bicarbonate in the Dog

The effect of nicotine upon pancreatic secretion of fluid and bicarbonate was studied in conscious dogs prepared with pancreatic and gastric fistulas. Secretion was stimulated either by intravenous infusion of exogenous secretin in various doses or by the endogenous release of secretin elicited by intraduodenal infusion of hydrochloric acid. Nicotine was administered to inhibit pancreatic secretion; the alkaloid was infused intravenously or applied topically to the duodenal mucosa. Intravenous infusion of nicotine inhibited pancreatic secretion stimulated by all doses of exogenous secretin and by endogenously released secretin. Intraduodenal nicotine inhibited pancreatic secretion stimulated by endogenously released secretin but not by intravenous secretin. The depression of exogenously stimulated pancreatic secretion by intravenous nicotine showed characteristics of competitive inhibition. Nicotine appears to inhibit pancreatic bicarbonate and water secretion by a direct action on that organ and also by decreasing the endogenous release of secretin from the duodenal mucosa. Nicotine did not have a significant effect on pancreatic protein output stimulated by either secretin or cholecystokinin.