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Pancreatic secretory response to intraileal amino acids
Abstract
Methods: Four dogs underwent total extrinsic denervation of the entire ileum. Thomas-like cannulas were placed into the stomach, duodenum (to collect pure pancreatic juice), and at the jejuno-ileal junction. Eight neurally intact control dogs received only the three fistulas. After recovery, in both sets of dogs, dose-response studies of the pancreatic secretory response to intraileal infusion with graded loads of tryptophan (0.12–10.0 mmol/h) were performed, given against an intravenous (iv) background of secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). On separate days, control experiments with intraileal infusion of 0.15 M NaCl were performed. Results: In both sets of dogs, iv secretin plus cerulein significantly (p Conclusions: 1) Extrinsic denervation of the entire ileum is a valuable preparation to study the role of nerves in the control of pancreatic exocrine secretion; 2) both in the intact and denervated animals the amino acid tryptophan induces an “ileal brake” of the hormonally stimulated pancreatic bicarbonate and protein output; 3) the extrinsic nerves of the ileum are probably not the dominant mediators of the inhibitory action of intraileal tryptophan but rather counteract this effect.
... The authors have shown that this dis- tance is easy to achieve in clinical practice with transnasal endoscopic place- ment of tube systems that are commercially available [69,70]. There is extensive literature that the presence of nutrients (in particular long chain fatty acids [71,72], carbohydrate [72], and amino acids [73]) in the ileum suppresses pancreatic secretion in humans, principally through release of GLP-I and peptide-YY (PYY) from ileal L-cells and neurotensin from N-cells [74]. Activa- tion of the ileal brake in this way may have the additional benefits by suppress- ing acute pancreatitis and inhibiting gastric acid secretion [74] and the need for NG decompression. ...
Nutritional support can improve the outcome from severe acute pancreatitis in two ways: first by providing the building blocks for tissue repair and recovery, and second, by modulating the inflammatory response and preventing organ failure, both of which are responsible for most of the morbidity and mortality associated with the disease. This review discusses the evidence on which these statements are based.
Objectives:
Despite the fact that the most effective treatment for morbid obesity today is gastric bypass surgery, some patients develop life-threatening nutritional complications associated with their weight loss.
Methods:
Here we examine the influence of the altered anatomy and digestive physiology on pancreatic secretion and fat absorption. Thirteen post Roux-en-Y gastric bypass (RYGB) patients who had lost >100 lbs in the first year following surgery and who gave variable histories of gastrointestinal (GI) dysfunction, were selected for study. Food-stimulated pancreatic enzyme secretion and GI hormone responses were measured during 2 h perfusions of the Roux limb with a standard polymeric liquid formula diet and polyethylene glycol marker, with collections of secretions from the common channel distal to the anastomosis and blood testing. Fat absorption was then measured during a 72 h balance study when a normal diet was given containing ~100 g fat/d.
Results:
Result showed that all patients had some fat malabsorption, but eight had coefficients of fat absorption <80%, indicative of steatorrhea. This was associated with significantly lower feed-stimulated secretion rates of trypsin, amylase, and lipase, and higher plasma peptide-YY concentrations compared with healthy controls. Five steatorrhea patients were subsequently treated with low quantities of pancreatic enzyme supplements for 3 months, and then retested. The supplements were well tolerated, and fat absorption improved in four of five patients accompanied by an increase in lipase secretion, but body weight increased in only three. Postprandial breath hydrogen concentrations were elevated with some improvement following enzyme supplementation suggesting persistent bacterial overgrowth and decreased colonic fermentation.
Conclusions:
Our investigations revealed a wide spectrum of gastrointestinal abnormalities, including fat malabsorption, impaired food stimulated pancreatic secretion, ileal brake stimulation, and bacterial overgrowth, in patients following RYGB which could be attributed to the breakdown of the normally highly orchestrated digestive anatomy and physiology.
Delayed gastric emptying (DGE) represents a significant cause for morbidity following pancreatoduodenectomy (PD). At a time when no specific and universally effective therapy exists to treat these patients, elucidating other potential (preventable or treatable) mechanisms for DGE is important. The aim of the manuscript was to test the hypothesis that ileal brake contributes to DGE in PD patients receiving jejunal tube feeding by systematically reviewing experimental and clinical literature. A series of clinically relevant questions were framed related to the potential role of the ileal brake in development of DGE post-PD and formed the basis of targeted literature searches. A comprehensive search of major reference databases from January 1980 to June 2015 was carried out which included human and animal studies. The ileal brake is a feedback loop neurally mediated by the vagus and sympatho-adrenergic pathways and hormonally by gut peptides including glucagon-like peptide-1, peptide YY (PYY), and neurotensin. The most potent stimulus for this inhibitory reflex is intra-ileal fat. There is evidence to indicate the role of an inhibitory reflex (on gastric emptying) mediated by PYY and CCK which, in turn, are stimulated by nutrient delivery into the distal small intestine providing indirect support to the role of ileal brake in post-PD DGE. The ileal brake is a likely factor contributing to DGE post-PD. While there has been no study to directly test this hypothesis, there is compelling indirect evidence to support it. Designing a trial that would answer such a question appears to be the most appropriate way forward.
The pancreas is a vital organ that plays a central role in digestion and metabolism of nutrients. Major functions of the pancreas include neutralization of gastric acid by secretion of bicarbonate into the duodenum; secretion of digestive enzymes into the duodenum for the breakdown of complex proteins, carbohydrates, lipids, and nucleic acids; and secretion of islet cell hormones into the circulation to control systemic metabolism of nutrients after absorption.
Conclusions:
In dogs, 1. Activation of cholecystokinin-receptors is needed for an adequate pancreatic bicarbonate response to secretin; 2. Cholinergic nerve fibers ending on M1-receptors are probably of little or no importance for the bicarbonate response to secretin in the given dose; 3. The bicarbonate response to tryptophan, given with a secretin background, is controlled by cholinergic M1-fibers and by cholecystokinin; 4. M1-fibers mainly mediate the bicarbonate response to low loads of tryptophan, whereas cholecystokinin controls the response to low and high loads of tryptophan; and 5. Both mediators interact in a synergistic manner.
Methods:
In six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol/kg/h), the cholecystokinin-receptor antagonist L-364,718 (0.025-0.1 mg/kg/h), and combinations of both on the pancreatic bicarbonate response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h).
Results:
Secretin significantly (p < 0.05) stimulated the pancreatic bicarbonate output above basal levels. All doses of L-374,718, but not telenzepine, significantly decreased the bicarbonate response to secretin by up to 64%. Additional administration of telenzepine together with L-364,718 had no further inhibitory effect on the secretin-stimulated bicarbonate output as compared to L-364,718 given alone. All loads of tryptophan significantly increased the bicarbonate output over that seen with secretin alone (= incremental bicarbonate response to tryptophan). Telenzepine significantly decreased the incremental bicarbonate response to the two lower loads (0.37-1.1 mmol/h) of tryptophan (by 82-124%); L-364,718 decreased the incremental bicarbonate response to all loads of tryptophan (by 50-118%). The incremental bicarbonate output, as well as the 180-min integrated bicarbonate response to all loads of tryptophan, were abolished by all combinations of both antagonists.
The pancreatic secretion of fluid, bicarbonate and protein in response to electrical stimulation of the vagus and splanchnic nerves, to exogenous and endogenous secretin and to various pharmacological agents was studied in anesthetized young pigs (21 kg). Vagal stimulation increased flow, bicarbonate output and protein output in a frequency dependent manner; the half maximal effective frequency was 2--4 Hz and the maximal effective frequency 12 Hz. The secretory response to vagal stimulation was potentiated by physiological elevations of the arterial concentration of secretin brought about by injection of secretin or by acidification of the duodenal bulb. Simultaneous stimulation of the splanchnic nerves strongly inhibited the response to vagal stimulation; splanchnic nerve stimulation alone had no demonstrable effect. The flow and bicarbonate response to vagal stimulation was unaffected by atropine, but abolished by hexamethonium. Protein output was strongly inhibited by both agents. The response to intraarterial infusion of acetylcholine resembled that elicited by vagal stimulation but it was smaller and it was completely abolished by atropine and unaffected by hexamethonium. Alpha- and beta-adrenergic blockade stimulated rather than inhibited the secretory response to vagal stimulation. The portal vein plasma concentration of secretin was not affected by vagal stimulation. The results indicate that the protein response, and the flow and bicarbonate response to vagal stimulation are not brought about by the same mechanism. An increased release of secretin is not involved. Peptidergic (VIP-containing) nerves may contribute.
We studied the factors which contribute to the increase in circulating pancreatic polypeptide concentrations which occur when food is eaten. Homogenized food, infused directly into the stomach, led to a marked increase in serum pancreatic polypeptide concentrations which was of similar magnitude in both normal subjects and in patients with duodenal ulcer. This response is unlikely to be attributed to gastrin or cholecystokinin released by food because intravenous gastrin and cholecystokinin failed to release pancreatic polypeptide in significant amounts. Food-stimulated pancreatic polypeptide release was unaffected by a previous truncal vagotomy, duodenal acidification, or cimetidine. On the other hand, the pancreatic polypeptide response to food was markedly inhibited by propantheline (P < 0.005). Gastric distention with glucose and saline significantly increased serum pancreatic polypeptide levels, although, compared to food, pancreatic polypeptide responses were small. Likewise, cephalic-vagal stimulation induced by modified sham feeding led to small but significant pancreatic polypeptide rises in normal subjects. Unlike the response to intragastric food, the pancreatic polypeptide response to sham feeding was reduced in vagotomized patients. We conclude that, although gastric distention and cephalicvagal stimulation contribute to the over-all pancreatic polypeptide response to eating, the majority of the response is caused by the presence of food per se in the gastrointestinal tract. It is likely that food in the stomach or small intestine sends a message to the pancreas, either via a nonvagal neural reflex or through the bloodstream, resulting in pancreatic polypeptide release. Because the pancreatic polypeptide response to food is inhibited by propantheline, it appears that a cholinergic pathway is involved.
Article de synthese traitant des effets de la somatostatine sur la regulation des fonctions exocrines du pancreas. Effets sur la secretion pancreatique non-stimulee (interdigestive) et stimulee; eau, bicarbonate et enzymes. Traitement des troubles pancreatiques. Effets chroniques de la somatostatine sur la secretion et la croissance du pancreas. Effets de la somatostatine sur la liberation de secretagogues pancreatiques. Mecanismes d'action.
We investigated the effect of perfusing carbohydrate into the ileum on postprandial pancreaticobiliary secretion and the relationships among carbohydrate in the ileum, pancreaticobiliary secretion, and gastric emptying. Eighteen healthy volunteers were intubated with a multilumen oroileal tube. A metal labeled with 111In-diethylenetriamine-pentaacetic acid (400 calories; 60% carbohydrate, 20% protein, 20% fat) was then infused into the stomach, and a carbohydrate solution (rice starch + glucose) was perfused into the terminal ileum at rates (mg/min) of 0 (saline; n = 6), 12.5 (n = 4), 25 (n = 4), 50 (n = 2), and 100 (n = 2). To prevent digestion of the carbohydrate in the ileum, an amylase inhibitor (3.3 mg/ml) was added to the perfusate used in half of the subjects. Postprandially, we measured outputs of amylase, trypsin, and bile acids in the duodenum, the amount of carbohydrate in the ileum, and gastric emptying. During the second postprandial hour the rate of gastric emptying was inversely related to the amount of carbohydrate in the ileum (p less than 0.01) and was directly correlated with pancreaticobiliary secretion (p less than 0.05). However, as the amount of unabsorbed carbohydrate in the ileum increased, the ratio of amylase to trypsin secretion increased (p less than 0.005). Postprandially carbohydrate in the ileum induces changes of upper-gut function that should increase digestion and absorption of carbohydrate since gastric emptying (and delivery of carbohydrate to the duodenum) slows and pancreatic amylase secretion increases relative to trypsin secretion and gastric emptying.
We used an amylase inhibitor preparation that markedly improves postprandial carbohydrate tolerance in humans to investigate the effects of decreased intraluminal amylase activity on digestion of starch and postprandial gastrointestinal and hormonal responses. Four fasting volunteers were intubated with an oroileal tube to obtain duodenal, jejunal, and terminal ileal samples. After intubation, subjects ingested 50 g of rice starch given with placebo; on the second day, starch was given with the amylase inhibitor. Compared with placebo, the amylase inhibitor significantly (p less than 0.05) reduced duodenal, jejunal, and ileal intraluminal amylase activity by more than 95% for 1-2 h; increased postprandial delivery of total carbohydrate (glucose polymers in particular) to the distal small bowel; increased breath hydrogen concentrations; decreased intestinal water absorption and increased distal intestinal volume delivery to the distal bowel; shortened duodenoileal transit time but doubled postprandial gastric emptying time; reduced the early postprandial plasma glucose rise by 85% and eliminated the late postprandial glucose fall to below fasting levels; and abolished postprandial plasma concentrations of insulin, C-peptide, and gastric inhibitory polypeptide. Postprandial trypsin output was not influenced. We conclude that more than 95% inhibition of amylase reduces dietary starch digestion within the small intestine and uptake of dietary starch from the small intestine, markedly decreases postprandial release of insulin and gastric inhibitory polypeptide, and may alter postprandial upper gastrointestinal motor function.
In two sets of 6 dogs with gastric and pancreatic fistulas, we studied the effect of atropine (14 nmol/kg.h i.v.) on the pancreatic secretory response to intravenous caerulein and to intraduodenal perfusion with tryptophan (both given with a secretin background) before and after stepwise removal of the extrinsic nerves of the pancreas, i.e., celiac and superior mesenteric ganglionectomy alone or truncal vagotomy alone and truncal vagotomy plus celiac and superior mesenteric ganglionectomy. Atropine significantly (p less than 0.05) depressed the protein output in the basal state and in response to secretin at each stage of innervation. The incremental protein response to caerulein was not altered by the various denervation operations nor by atropine. Truncal vagotomy alone significantly decreased the incremental protein response to low (0.12, 0.37, and 1.1 mmol/h) but not high loads of tryptophan. Ganglionectomy in combination with vagotomy did not further depress the incremental protein response to low loads of tryptophan. Atropine significantly reduced the incremental protein response to low loads of tryptophan only in intact innervated animals. Ganglionectomy alone did not alter the incremental protein response to any load of tryptophan. Ganglionectomy, truncal vagotomy, and atropine did not alter basal or tryptophan-stimulated levels of plasma cholecystokininlike immunoreactivity. We conclude that (a) neither the extrinsic nor the intrinsic cholinergic pancreatic nerves modulate the protein response to caerulein; (b) the sympathetic pancreatic nerves do not mediate the response to tryptophan; (c) the protein response to intraduodenal tryptophan is at least in part mediated by long, cholinergic, enteropancreatic reflexes with both afferent and efferent fibers running within the vagus nerves; and (d) release of cholecystokinin by intestinal tryptophan is not under cholinergic or splanchnic control.
Studies were carried out in 25 healthy male volunteers to investigate the effect of ileal infusion of solutions of different nutrient composition and osmolality on the profiles of a radiolabeled solid meal emptying from the stomach. Ileal infusion of a 50% corn oil emulsion or a 20% oleic acid emulsion slowed the rate of gastric emptying compared with ileal infusion of isotonic saline (0.9%). In contrast, infusion of either hypertonic saline (430 mosmol), distilled water, or isotonic solutions containing protein hydrolysate (8 g%) or glucose (50 mM) had no effect on the gastric emptying profile. These experiments support the hypothesis that the presence of unabsorbed lipid or fatty acids in the distal small intestine may delay gastric emptying, but suggest that sugars and proteins are ineffective. As infusion of both protein hydrolysates and lipid into the ileum can delay small bowel transit in humans, the data suggest that ileal regulation of gastric emptying and small bowel transit may be mediated by different mechanisms.
We determined the effects of three different doses of pancreatic polypeptide (50, 200, and 800 pmol X kg-1 X h-1) on pancreatic responses to graded doses of intravenous secretin, caerulein, and bethanechol and intraduodenal HCl, L-phenylalanine, and sodium oleate in dogs. The two lowest doses of pancreatic polypeptide (PP), which produced blood levels lower than measured after a meal, significantly inhibited the pancreatic responses to secretin, caerulein, HCl, and L-phenylalanine; the highest dose of PP inhibited the responses to bethanechol and sodium oleate. There was no difference in the degree of inhibition of bicarbonate or protein secretion caused by pancreatic polypeptide. With secretin, caerulein, bethanechol, and sodium oleate, inhibition was most pronounced against lower doses and was surmountable with higher doses of these stimulants. Inhibition of responses to HCl and L-phenylalanine was observed at all doses of these stimulants. Inhibition of the exocrine pancreatic secretory responses to six different stimulants by PP suggests that this hormone may play an important role in regulation of postprandial pancreatic secretion.
The small bowel transit time of 100 ml of lactulose solution infused at the ligament of Treitz was measured by breath hydrogen excretion in paired studies carried out in 43 healthy volunteers during infusion (1.2 ml/min) of equal volumes (100 ml) of isotonic solutions of either fat emulsion (Intralipid, Prosparol, or Calogen), protein hydrolysate, glucose, or saline into either the jejunum (90 cm from the teeth), ileum (205 cm from the teeth), or colon (350 or 400 cm from the teeth). Ileal infusion of Intralipid or protein hydrolysate resulted in significant delays in small bowel transit time (125 +/- 21 min and 71 +/- 11 min, respectively) compared with infusion of saline (50 +/- 3 min; p less than 0.02 and p less than 0.05). These delays were not associated with any significant alteration in plasma levels of neurotensin or enteroglucagon. Small bowel transit time was unaffected by infusion of nutrients into the colon or jejunum, although jejunal infusion of Intralipid increased the plasma levels of enteroglucagon and neurotensin (p less than 0.01 and p less than 0.02, respectively) after the start of lactulose infusion. In a separate series of paired experiments, infusion of Intralipid into the ileum in 5 volunteers significantly delayed the transit of a solid test meal labeled with 25 microCi of 99mTc-sulfur colloid through both the stomach and small intestine. These data support the existence of a mechanism whereby the presence of unabsorbed food in the ileum may enhance absorption by delaying the passage of food through the small intestine.
In dogs with a fistula of the intact pancreas and a transplanted portion of pancreas, we studied the effect of atropine on the pancreatic secretory response to intravenous caerulein and to intestinal perfusion with tryptophan, both given with a secretin background. Atropine (50 micrograms . kg-1 given as an intravenous bolus injection followed by 20 micrograms . kg-1 . h-1 iv infusion) depressed bicarbonate and protein secretion from intact pancreas during stimulation by secretin alone (250 ng . kg-1 . h-1) but did not suppress the increment in bicarbonate secretion in response to caerulein or tryptophan given against the secretin background. In intact pancreas, atropine suppressed protein secretion in response to tryptophan but not in response to caerulein. Atropine had no significant effect on the secretion of bicarbonate and protein from transplanted pancreas in response to secretin, caerulein, or tryptophan. Thus, the only significant effect of atropine on bicarbonate and protein secretion from intact and transplanted pancreas in response to intravenous caerulein or intraduodenal tryptophan, both given against a background of secretin, was inhibition of the protein response to tryptophan in the intact pancreas. These findings are compatible with the hypothesis that pancreatic protein secretion in response to intraduodenal tryptophan is mediated in part by a cholinergic enteropancreatic reflex.
The relative potency of two drugs may be estimated from a small experiment in which all K doses of each drug are given in order of increasing dose level to each of n aminals at one testing session. Fiducial limits are often estimated from Fieller's theorem, with the (2K - 1)(n - 1)-degree-of-freedom error term obtained from a two-way analysis of variance. Monte Carlo results indicate that this method can yield limits which are far too narrow when there is serial correlation between successive doses. The jackknife confidence limits are found to behave well for the models investigated.
In six conscious dogs with gastric and pancreatic Thomas fistulas, we studied the pancreatic bicarbonate response to intravenous bolus injections of synthetic secretin dissolved either in 5 ml of 0.15 M NaCl alone or in the same amount of NaCl to which dog albumin had been added, to give a 0.1% solution. The pancreatic bicarbonate (micromol . 10 min-1) response to the four lowest doses of secretin (12.5, 25, 50, 100 ng . kg-1) used was significantly (p less than 0.05) higher when secretin was dissolved in NaCl plus albumin than in NaCl alone. The pancreatic response to higher doses of secretin (200, 400, 800, 1600 ng . kg-1) was not significantly altered by the addition of albumin. The D50 of secretin was about 2.6 times greater in the absence than in the presence of albumin. This study suggests that albumin should be added to dilute solutions of secretin to preserve biological activity.
To answer the questions if the type of continuous dose-response technique influences the pancreatic secretory response to intraduodenal tryptophan and if the M1-receptor antagonist telenzepine influences the intestinal absorption of tryptophan, we determined, in 12 conscious dogs with chronic gastric and duodenal fistulas, pancreatic bicarbonate and protein secretion and tryptophan plasma concentrations following intraduodenal tryptophan perfusion using two dose-response techniques. With an ascending continuous dose-response technique (aDRT), tryptophan was perfused in loads ranging from 0.12 to 10.0 mmol h-1, starting with the lowest load and tripling it every 45 min. With the descending continuous dose-response technique (dDRT), the order of tryptophan loads was reversed, with the highest load being given first. All studies were done on a fixed background of intravenous secretin (20.5 pmol kg-1 h-1) and repeated in the presence of the anticholinergic M1-receptor antagonist telenzepine (243 nmol kg-1 h-1). The bicarbonate and protein response as well as tryptophan plasma concentrations to the same loads of tryptophan did not differ significantly between the two techniques. Using both techniques, telenzepine significantly (p < 0.05) inhibited the overall pancreatic protein response by 65% (dDRT) to 81% (aDRT). The overall bicarbonate response was only numerically, and not statistically significantly, inhibited by telezepine. Tryptophan plasma concentrations after duodenal perfusion with tryptophan were neither influenced by the order of tryptophan loads nor altered by telenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)
While the duodenum controls pancreatic exocrine secretion mainly via stimulatory mechanisms, intraileal and intracolonic nutrients have mainly inhibitory effects on the postprandial and interdigestive pancreatic secretion, which are described in particular. The inconsistent findings in dogs in contrast to other species (cat, rat, human) referring to the effects of intraileal nutrients are discussed. Possible mechanisms for the neurohormonal mediation of the effects of intraileal and intracolonic nutrients on the pancreatic secretion as well as the possible physiological importance of these effects are discussed.
Previously we showed that carbohydrate (CHO) in the ileum slowed gastric emptying and increased pancreatic amylase secretion relative to that of other enzymes. Our aim here was to determine if extrinsic innervation of the jejunoileum participates in the CHO-induced ileal modulation of postprandial upper gut function. Six dogs were studied before and 2-3 weeks after in situ neural isolation of the jejunoileum (complete extrinsic denervation). Gastric emptying (GE) and pancreatic amylase secretion were quantitated for 4 h after a 300-ml meal containing 3H-PEH (liquid marker) and 99mTc sulfur colloid cooked with eggs (solid marker). Coincident with feeding, we started a distal ileal infusion of 150 mM NaCl or 40 mg.min-1 CHO. Extrinsic denervation abolished the slowing of GE of liquids and solids and the augmented increase in amylase and trypsin in relation to solid emptying seen in the neurally intact dogs prior to denervation. Denervation also abolished the decrease in total pancreatic exocrine secretion in response to ileal CHO. Increases in plasma concentrations of peptide YY (PYY) were correlated temporally with decreased GE of solids and increased exocrine secretion during ileal CHO in neurally intact dogs, but no increases in PYY release occurred after extrinsic denervation. Extrinsic denervation of the jejunoileum abolished the effect of ileal CHO on GE of liquids and solids, the decrease in total amylase secretion during ileal CHO, and the relative increase in enzyme secretion expressed as total enzyme output per percentage solid marker emptied. Extrinsic innervation of the jejunoileum mediates ileal modulation of GE and the relationship of amylase secretion to GE of solids. The mechanism of this effect may be via neurally mediated release of PYY.
It is assumed that in humans pancreatic and gastrointestinal motor responses to a meal are coordinated and regulated mainly by duodenal nutrient exposure. On the other hand, there is evidence that the distal intestine may participate in the regulation of gastrointestinal functions. The aim of this study was to compare human pancreatic and intestinal motility responses to a meal and to correlate them with nutrient exposure of the proximal and distal intestine. After intubation with an oroileal multilumen tube for marker perfusion, duodenal and ileal aspiration, and intestinal manometry, 14 healthy subjects received a mixed test meal (1,257 kJ). Intraluminal nutrient concentrations, enzyme activities, and small intestinal motility were analyzed for 6 h postprandially. Duration of duodenal nutrient exposure was 3.4 +/- 0.2 h, and duration of pancreatic enzyme response and fed motor pattern was 2.5 +/- 0.2 and 3.5 +/- 0.3 h, respectively. Durations of pancreatic secretory and motor responses were correlated (P < 0.05), but neither duration of digestive secretory nor of motor activity correlated with that of prandial duodenal nutrient concentrations. By contrast, they were associated with the relative increase in ileal nutrient delivery late postprandially (P < 0.05). Physiological late postprandial delivery of nutrients to distal intestinal sites is correlated with the termination of digestive pancreatic and motor responses and may participate in their control.
In two sets of dogs with gastric, duodenal, and jejunal fistulas, we studied the effect of atropine (14 nmol/ kg/h) on the pancreatic secretory response to intrajejunal tryptophan (0.12-10.0 mmol/h; given against a secretin background) before (n = 7) and after extrinsic denervation of the jejunoileum (orthotopical autotransplantation; n = 6). Plasma levels of cholecystokinin were determined by radioimmunoassay. The incremental bicarbonate response to tryptophan was not significantly different between the two sets of dogs. Atropine had no effect on the incremental bicarbonate response to tryptophan. In both sets of dogs, intrajejunal tryptophan caused a dose-dependent increase in pancreatic protein output, which was reduced by atropine. The tryptophan-stimulated levels of plasma cholecystokinin were not significantly altered by denervation and or atropine. We conclude that in dogs (1) intrajejunal tryptophan stimulates pancreatic bicarbonate and protein secretion via release of hormones, (2) extrinsic denervation of the jejunoileum does not significantly alter the incremental bicarbonate and protein responses to intrajejunal tryptophan, (3) the cholinergic intrinsic nerves of the jejunoileum and the hormone cholecystokinin are probably involved in control of the pancreatic protein response to tryptophan, and (4) the release of cholecystokinin by intrajejunal tryptophan does not depend on the extrinsic and intrinsic cholinergic nerves of the jejunoileum.
In six conscious dogs we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol.kg-1.h-1), the cholecystokinin (CCK) antagonist L-364,718 (0.025-0.1 mg.kg-1.h-1), and combinations of both on the pancreatic secretory response to intraduodenal tryptophan, given against a secretin background before and after truncal vagotomy. Before vagotomy, the higher doses of telenzepine and of L-364,718 significantly (P < 0.05) decreased the protein response to tryptophan by up to 97%. After vagotomy, all doses of L-364,718 abolished the protein response, whereas telenzepine had no further effect. Before and after vagotomy, all combinations abolished the protein response. The plasma CCK-like immunoreactivity basally, during secretin, and in response to tryptophan was not altered by vagotomy, telenzepine, and/or L-364,718. These findings indicate that in dogs 1) potentiation exists between M1 receptors and CCK for stimulation of the pancreatic enzyme response to intraduodenal tryptophan, 2) the cholinergic fibers of the enteropancreatic reflex activated by tryptophan run within the vagus nerves and end at least in part on M1 receptors, 3) CCK acts in part independently of the vagal nerves, and 4) the CCK release by intestinal tryptophan is not influenced by vagotomy, telenzepine, and/or L-364,718.
The present report gives a review about the localization, release and gastrointestinal actions of peptide YY in different animal species and in humans. Possible mechanisms of action, the physiological and pathophysiological significance of peptide YY and the role of peptide YY 3-36 are discussed. Finally, unanswered questions are specified.
Ileal inhibitory effects on pancreatic enzyme output are also demonstrable during exogenous, cholinergic stimulation of exocrine pancreatic secretion. These findings support the hypothesis that direct inhibition of cholinergic systems may be involved in the ileal inhibitory effects on pancreatic enzyme secretion. Furthermore, glucagon-like peptide-1 (GLP-1) may play a role in the mediation of the ileum-induced effects.
Ileal carbohydrate perfusion inhibits endogenously stimulated exocrine pancreatic secretion in humans. Our aim was to investigate if ileal perfusion of carbohydrates exerts similar effects on exogenously stimulated pancreatic enzyme output, i.e., if the inhibitory mechanisms are reproducible during direct, cholinergic stimulation of the exocrine pancreas. Furthermore, we sought to clarify the role of the potential humoral mediators (GLP-1) and peptide YY (PYY).
Eight healthy fasting volunteers were intubated with an oroileal multilumen tube system for aspiration of duodenal juice and perfusion of test solutions. Exocrine pancreatic secretion was stimulated by a continuous i.v. infusion of the cholinergic agonist carbachol. Additionally, the ileum was perfused for 15-min intervals with either carbohydrates (total load: 18 g) or saline as control. Blood samples for determination of GLP-1 and PYY were taken before the beginning of exogenous stimulation and before and after ileal perfusion.
Exogenously stimulated pancreatic enzyme secretion was significantly inhibited by additional ileal carbohydrate perfusion (p < 0.05), whereas ileal saline had no effect. Moreover, plasma levels of GLP-1 increased significantly (p = 0.004) after ileal perfusion of carbohydrates, but not after saline. PYY plasma concentrations remained unchanged after both ileal perfusates.
This report presents a review of the historic and current methods for performing pancreatic exocrine studies in intact animals. Special emphasis is given to the various surgical procedures--pancreatic fistulas, duodenal pouches, and duodenal fistulas--and practice of collecting pancreatic secretion in dogs. Procedures in other animal species--rat, cat, pig, rabbit, cattle, sheep, and horse--also are specified. The advantages and disadvantages, as well as the indications and limitations of the distinct methods, are discussed.
1. Electrical stimulation of the cut peripheral end of the splanchnic nerves results in a biphasic change in electrical conductance measured across the tail of the pancreas. A phase of decreased conductance is followed by a more prolonged phase of increased conductance.
2. Simultaneous measurements of pancreatic blood flow indicate that the phase of decreased conductance occurs as a result of vasoconstriction, whilst the phase of increased conductance is due to vasodilatation.
3. The initial phase of decreased conductance and vasoconstriction is abolished by α‐receptor blocking agents such as phenoxybenzamine and the phase of increased conductance blocked by β‐receptor blocking agents such as pronethalol.
4. Short periods of electrical stimulation applied to the splanchnic nerves result in a secretion of amylase and a reduction in the volume rate of secretion.
5. When the vasoconstrictor response was abolished by phenoxybenzamine, nerve stimulation still reduced the rate of secretion, suggesting that the inhibitory effect is in part due to a direct action of the secretory cells.
6. After bretylium tosylate, splanchnic nerve stimulation no longer produced vasomotor changes in the pancreas and the inhibitory effect on the volume response was converted to one of augmentation, but the secretion of enzymes was unaffected.
7. The secretion of amylase on splanchnic stimulation was abolished by intravenous injection of atropine, suggesting that a cholinergic mechanism is involved.
8. Noradrenaline did not mobilize pancreatic enzymes.
Extrinsic and intrinsic innervation of the pancreas: mediators of pancreatic exocrine secretion
- E Niebergall-Roth
- H-J Krammer
- R Radke
- Singer
Evidence for direct inhibition of human pancreatic enzyme secretion in response to ileal nutrients
- P Layer
- D Hermsmeier
- A Unger
- G Gröger
- Goebell
Das terminale Ileum als Koregulator der zyklischen interdigestiven Pankreassekretion beim Menschen
- P Layer
- G Gröger
- D Grandt
- Leelamma
Alpha-adrenergic receptors do not mediated ileum-induced inhibition of pancreatic secretion
- P Layer
- H Binczyk
- G Gröger
- Goebell
Differential responses of human pancreatic and biliary secretion to graded ileal lipid perfusion
- J Keller
- H Conrads
- H Goebell
- Layer