Pancreaticobiliary Secretion Research Articles

Role of intraduodenal proteases in plasma cholecystokinin and pancreaticobiliary responses to protein and amino acids

BACKGROUND & AIMS: The role of small intestinal proteolytic activity in the regulation of upper gastrointestinal function in humans is poorly understood. The aim of this study was to determine the importance of proteolytic activity for protein- or amino acid-induced cholecystokinin release and pancreaticobiliary secretion. METHODS: In 9 healthy subjects, saline was perfused intraduodenally for 3 hours either with or without the synthetic protease inhibitor camostate. During the last hour, albumin or amino acids in the same molecular composition as albumin were also perfused. RESULTS: Perfusion with camostate, in concentrations that abolished intraduodenal proteolytic activity, had no effect on unstimulated plasma cholecystokinin concentrations or gallbladder emptying, but markedly (P < 0.05) increased unstimulated pancreatic enzyme output. Perfusion with protein distinctly stimulated cholecystokinin release, gallbladder emptying, and pancreatic enzyme output (P < 0.05). Perfusion with camostate resulted in significantly lower protein-stimulated plasma cholecystokinin, gallbladder, and pancreatic enzyme responses (P < 0.05). Perfusion with amino acids also stimulated plasma cholecystokinin, gallbladder emptying, and pancreatic enzyme output (P < 0.05). Camostate did not inhibit these values. CONCLUSIONS: This study shows that appropriate digestion of protein is required to stimulate plasma cholecystokinin release, gallbladder emptying, and pancreatic enzyme secretion in humans. (Gastroenterology 1996 Feb;110(2):567-75)

Importance of gastrin-releasing peptide on acid-induced secretin release and pancreaticobiliary and duodenal bicarbonate secretion.

Exogenous gastrin-releasing peptide (GRP) stimulates the release of secretin from the small intestine and pancreaticobiliary bicarbonate secretion in pigs. As acid is the principal stimulant of secretin release, the purpose of this study was to examine the importance of GRP in acid-induced secretin release and to determine whether GRP contributes to the regulatory function of acid-induced pancreaticobiliary bicarbonate secretion in anaesthetized pigs. Intravenous infusion of GRP (500 pmol/kg.h) increased significantly portal vein plasma concentrations of secretin from 1.3 to 5.4 pmol/l and GRP from 0.5 to 340 pmol/l, pancreatic bicarbonate secretion from 0.01 to 5.9 mmol/h, and hepatic bicarbonate secretion from 0.3 to 3.3 mmol/h, whereas duodenal mucosal bicarbonate secretion remained unchanged. Intravenous infusion of the GRP antagonist BIM-26226 completely abolished the GRP-induced secretin release and pancreatic and hepatic bicarbonate secretion. Furthermore, repeated infusions of GRP did not cause desensitization, and BIM-26226 therefore proved to be an effective GRP antagonist. Duodenal perfusion with acid (pH 1.5, 3.8 mmol/h) significantly increased portal vein plasma concentrations of secretin from 0.4 to 2.8 pmol/l, pancreatic bicarbonate secretion from 0.005 mmol/h to 0.19 mmol/h, hepatic bicarbonate secretion from 0.63 to 2.17 mmol/h, and duodenal mucosal bicarbonate secretion from 0.1 to 1.20 mmol/h. Of importance, infusion of BIM-26226 did not significantly alter the effect of intraduodenal acidification on plasma secretin release and pancreaticobiliary and duodenal bicarbonate secretion. Thus, we conclude that GRP likely plays an insignificant role in a possible peptidergic regulation of acid-induced intestinal secretin release and that GRP has no regulatory function in acid-induced pancreaticobiliary bicarbonate secretion. Furthermore, GRP has no effect on duodenal bicarbonate secretion.

Intraileal carbohydrate regulates canine postprandial pancreaticobiliary secretion and upper gut motility

Background & Aims: The effect of nutrients in the distal small intestine or colon on postprandial upper gut function is incompletely understood. The aim of this study was to determine if carbohydrate in the ileum or proximal colon of dogs affects postprandial pancreaticobiliary secretion, gastrointestinal transit, and circulating concentrations of certain gastrointestinal regulatory peptides. Methods: Seven dogs were prepared with permanent infusion and aspiration catheters in the duodenum and ileum and an infusion catheter in the cecum. Coincident with eating a meal containing liquid and solid markers, ileal or colonic (n = 5 dogs for each) infusions were begun of isosmolar 0.9% NaCI or carbohydrate in a 3:1 ratio of starch to glucose. Pancreatic enzyme output, bile acid delivery, gastrointestinal transit, and plasma concentrations of pancreatic polypeptide, neurotensin, and peptide YY were measured for 6 hours postprandially. Results: Carbohydrate infusion in the ileum, but not in the proximal colon, increased amylase secretion and plasma peptide YY, slowed gastric emptying of liquids and solids, slowed small intestinal transit, and decreased bile acid delivery into the duodenum ( P < 0.05 in each). Conclusions: Carbohydrate in the ileum regulates postprandial exocrine pancreatic enzyme secretion and other postprandial upper gut functions. Peptide YY may play a role in this regulation.

Bombesin stimulates mucosal growth in jejunal and ileal Thiry-Vella fistulas.

The authors determined whether the trophic effects of bombesin (BBS) on the small bowel mucosa are mediated by either nonluminal factors or endogenous luminal secretion. The gut hormone bombesin stimulates growth of small bowel mucosa. The mechanisms responsible for this trophic effect are not known. Rats underwent construction of a Thiry-Vella fistula (TVF) of either the jejunum or ileum. On postoperative day 10, the two groups were subdivided to receive either saline (control) or bombesin (10 micrograms/kg, subcutaneously, three times a day). After 14 days, rats were killed and the TVF was removed. The mucosa was scraped and weighed, and DNA and protein content was determined. Bombesin significantly increased mucosal weight and DNA and protein content of both the jejunal and ileal TVF compared with the control rats. Bombesin-mediated stimulation of small bowel mucosal growth is mediated by factors that are independent of luminal contents and pancreaticobiliary secretion. Bombesin may prove to be an important enterotrophic factor for gut mucosal proliferation.

The effect of gastrin-releasing peptide on porcine pancreaticobiliary bicarbonate secretion is mediated by secretin.

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

Neurohormonal control of the exocrine pancreas

Increasing numbers of peptide hormones appear to stimulate pancreatic enzyme secretion via vagal cholinergic pathways. Studies in rats indicated that cholecystokinin at physiologic levels stimulates pancreatic secretion via a capsaicin-sensitive afferent vagal pathway. Similar cholinergic dependency was observed in other stimulatory peptides such as neurotensin and adenylate cyclase activating polypeptide. Recent human studies further confirmed the existence of a feedback mechanism between cholecystokinin release and pancreatico-biliary secretion. Cholecystokinin receptor blockade resulted in enhancement of postprandial plasma cholecystokinin levels but had no effect on basal plasma cholecystokinin levels. Under fasting conditions, however, cholecystokinin receptor blockade increased cholecystokinin synthesis but not its release. Further studies in rats indicated that dietary problems in the intenstine modulate feedback regulation of cholecystokinin release by luminal trypsin inhibitors. Endocrine and exocrine pancreatic interaction has important functional and clinical significance. Studies in rats showed that insulin exerted a direct potentiating effect on pancreatic acinar cells by increasing Na+, K+-ATPase activity. In isolated rat pancreas, somatostatin-enhanced arginine evoked pancreatic secretion by inhibiting the release of glucagon under hypoglycemic conditions. However, in euglycemic conditions somatostatin inhibited pancreatic secretion by acting at a central vagal site. Two separate laboratories provided convincing evidence that NO (nitric oxide), produced by NO synthase mediated he stimulation by carbachol of cyclic GMP formation, which in turn evoked Ca2+ influx in pancreatic acinar cells. The activity of NO synthase was regulated by internal Ca2+ stores. This provides a novel mechanism to explain Ca2+ transport in pancreatic acinar cells. In the field of pancreatic growth and proliferation, the demonstration that concomitant expression of high levels of fibroblast growth factors (FGFs) and FGF receptors in pancreatic cancer cells was associated with advanced clinical stages and poor prognosis suggests that these growth factors may contribute to progression of the pancreatic cancer by allowing excessive autocrine and paracrine growth stimulation.

The Ileum and Carbohydrate-Mediated Feedback Regulation of Postprandial Pancreaticobiliary Secretion in Normal Humans

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.

Morphine Inhibits Secretion of Bicarbonate from the Human Duodenal Mucosa: Possible Role of Endogenous Opioids in the Regulation of Human Duodenal Mucosal Bicarbonate Secretion

Mucus and bicarbonate secreted from the epithelium are thought to be important for the protection of the duodenal mucosa against acid and pepsin, but so far little is known about the regulation of human duodenal mucosal bicarbonate secretion. After isolating a segment of the proximal human duodenum from gastric and pancreaticobiliary secretion we quantified the secretion of bicarbonate from the human duodenal mucosa. The method was evaluated by measurements of basal and prostaglandin E1 analogue-stimulated bicarbonate secretion. The duodenal mucosal bicarbonate secretion was inhibited 70% after intravenous infusion of morphine in a dose of 73.6 micrograms/kg/h and increased after intravenous administration of naloxone. Thus, the inhibition is most likely mediated by mu-receptors, and the results suggest a role of endogenous opioids in the regulation of the secretion of bicarbonate from the human duodenal mucosa.

Duodenal Disappearance Rate of Acid during Inhibition of Mucosal Bicarbonate Secretion

In order to investigate the relation between duodenal mucosal and pancreaticobiliary bicarbonate secretion, we have studied the effect of inhibition of mucosal bicarbonate secretion by indomethacin on the disappearance rate of acid and the concomitant plasma secretin concentrations. 10 healthy subjects were studied twice, with and without indomethacin pretreatment. By means of a double-lumen tube the duodenum was perfused with increasing amounts of acid (0, 3.0, 6.0 and 9.5 mmol/h) and the disappearance rate of acid, pH of duodenal aspirate and plasma secretin were measured. In both experiments nearly all acid, even at the highest acid load, disappeared (pH greater than 6). Inhibition of the duodenal mucosal bicarbonate secretion did not decrease the acid-neutralizing capacity of the human duodenum. In fact, the disappearance rate of acid at the highest acid load was a little greater when mucosal bicarbonate secretion had been inhibited than when not (10.3 +/- 0.5 vs. 9.2 +/- 0.2 mmol/h). The pancreaticobiliary secretion of bicarbonate, as judged by plasma secretin concentrations, increased, however, earlier when mucosal bicarbonate secretion had been inhibited than when not (3.7 vs. 3.0 pmol/l at an acid load of 6.0 mmol/h). This indicates that bicarbonate from the duodenal mucosa normally plays a role in the in lumen neutralization of acid in the human duodenum.

Short Bowel Syndrome: Intestinal Adaptation and Medical Therapy

Short bowel syndrome is a clinical entity, a consequence of significant loss of intestinal surface area, and manifests a variable picture of diarrhea, steatorrhea, malabsorprion and weight loss. Previously high mortality rates have been reduced by the early use of parenteral nutrition and have subsequently resulted in increased survival and prevalence of the condition. Ultimate patient survival is dependent on the intrinsic adaptive ability of residual intestine and this, in turn, is dependent upon length, type, functional state and the presence or absence of an ileocecal valve. The mechanisms of intestinal adaptation are not entirely understood; however, they can be grouped into three broad categories: luminal nutrition, hormonal factors, and pancreaticobiliary secretion. Medical treatment of short bowel syndrome remains supportive and centres around the control of three pathophysiological defects: decreased intestinal transit time, gastric hypersecretion, and reduced functional mucosal surface area.

Fat and pancreatic secretion.

In 10 healthy volunteers we investigated the effects of intraduodenal oleic acid at various concentrations (0-40 mM) and at various degrees of emulsification on pancreaticobiliary secretion and the release of secretin and cholecystokinin (CCK) into plasma. We found that the release of the two hormones was directly related to the dose of fat and to the degree of emulsification. The threshold of CCK release (and amylase output) was low in comparison with the threshold for secretin release (and bicarbonate or volume output). When the degree of emulsification of the fat was increased, no simple relation was observed between hormone levels and pancreatic exocrine secretion. The output of bile salts was identical at various fat concentrations. We conclude that both secretin and CCK are dose-dependently released by emulsions of oleic acid in normal man and that the thresholds for release are probably different.

Comparative effects of CCK receptor antagonists on rat pancreatic secretion in vivo

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of intraduodenal chenodeoxycholic acid on secretory and pressure activity of the stomach and duodenum

ABSTRACTThe influence of duodenal infusion of bile acid at a concentration similar to that in the common bile‐duct (50 mmol/1) on antroduodenal motility, duodenogastric reflux, gastric and duodenal secretion was studied in 10 healthy volunteers. Intraluminal pressures were recorded in the antrum and the first and second parts of the duodenum. Gastric and distal duodenal contents were collected by continuous low pressure sump aspiration during infusion of either saline or chenodeoxycholic acid (CDC) into the second part of the duodenum. Values for duodenogastric reflux and gastric and duodenal secretion were calculated with reference to the recovery of two non‐absorbable markers infused into the stomach and second part of the duodenum. Each volunteer received at least 3 h of saline infusion and 2 h of CDC infusion.During saline infusion, duodenogastric reflux varied with the migrating motor complex (MMC), being statistically greater at the end of duodenal phase III activity than at other times (P&lt;0.05). Infusion of CDC abolished the MMC and inhibited antral contractions but the amount of reflux was not increased compared with the saline period. Infusion of CDC also produced marked increases in measured bicarbonate (P&lt;0.001), trypsin (P&lt;0.001), phospholipase A2 (P&lt;0.05) and endogenous total bile acid (P&lt;0.05) in the duodenum, although gastric acid secretion was unaffected. These findings suggest that bile acid may regulate gastroduodenal motor activity and pancreaticobiliary secretion.

Effect of Trypsin on the Hormonal Regulation of the Fat-Stimulated Human Exocrine Pancreas

To study the effects of trypsin on the pancreaticobiliary secretion and the release of secretin and cholecystokinin (CCK) to plasma, seven normal subjects were stimulated twice with duodenal perfusates containing 20 mM oleic acid (pH 6.0) with and without 1 g of bovine trypsin added per liter. In addition, six patients with advanced pancreatic insufficiency who received only the oleic acid were compared with eight normal subjects. The concentrations of secretin and CCK in plasma and the pancreatic enzyme and volume secretions were unaffected by the addition of trypsin, but the initial bile acid output and the bicarbonate secretion in the period after gallbladder emptying were reduced during perfusion with trypsin. The severely reduced enzyme secretion in chronic pancreatitis did not influence the basal or oleic acid-stimulated concentrations of the hormones in plasma. The study does not support the hypothesis of a trypsin-mediated negative feedback control of human pancreatic enzyme secretion. Furthermore, the reduced duodenal output of bicarbonate found in response to trypsin is not explained by changes in the release of secretin or CCK.

Plasma secretin, plasma cholecystokinin, pancreaticobiliary secretion, and fat absorption: effect of duodenal osmolality and polysorbate 80.

In 20 normal persons we investigated the effects of duodenal osmolality on the release of secretin and cholecystokinin (CCK), pancreaticobiliary secretion, and fat absorption after intestinal infusion of emulsified oleic acid (pH 6.0). The release of CCK was found to be unaffected by the changes in osmolality, whereas the plasma levels of secretin were affected in parallel with volume and bicarbonate secretion. An inverse relation was found between fatty acid absorption and release of secretin and bicarbonate secretion but not between fatty acid absorption and release of CCK. It is suggested that the secretin and CCK cells respond differently to emulsified oleic acid.

The significance of plasma CCK and secretin in the oleate-stimulated pancreatico-biliary secretion in man

In eight normal persons the plasma levels of secretin and cholecystokinin (CCK) measured after intraduodenal oleate were reproduced by intravenous (i.v.) infusion of synthetic secretin (3.4 pmol.kg-1.h-1) and CCK-8 (17.5 pmol.kg-1.h-1), either alone or in combination. Using an indicator dilution technique, the combined infusions of the two hormones were found to account for all the pancreatico-biliary secretion of amylase, bicarbonate, bile salts and volume elicited in response to intraduodenal oleate, pH 6. Furthermore, the bicarbonate secretion and the flow rate elicited by secretin were augmented by CCK, whereas no augmentation was found with regard to the CCK-stimulated enzyme and bile salts output.

Concentrations of secretin and CCK in plasma and pancreatico-biliary secretion in response to intraduodenal acid and fat.

To study the effect of emulsified oleic acid on pancreatic secretion and concentrations of secretin and cholecystokinin (CCK) in plasma, eight normal subjects received three sets of duodenal perfusates containing peptone pH 6.0 or pH 2.7, with and without 20 mM oleic acid. Pancreatic secretion was measured by an indicator dilution technique. At pH 6.0, peptone and oleic acid was about as effective as peptone pH 2.7 in stimulating secretin release. However, oleic acid in addition produced a three-fold increase in plasma CCK and was five times as effective as pH 2.7 in stimulating duodenal flow. Also, at pH 2.7, oleic acid augmented pancreatic secretion and concentrations of CCK and secretin in plasma. Duodenal output of amylase and bile salts was independent of the pH of infusate. Low pH alone was a very weak stimulant of CCK release and did not stimulate output of amylase and bile. Emulsified oleic acid is a potent releaser of secretin and CCK and augments the acid-induced pancreatic secretion.

Human duodenal mucosal bicarbonate secretion: Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E1 analogue

The factors responsible for prevention of duodenal mucosal injury are not known. This series of experiments was performed to determine whether the human duodenum secretes bicarbonate that could prevent mucosal damage. To isolate a 4-cm segment of proximal (i.e., the duodenal bulb) or distal duodenum free of contamination from either gastric or pancreaticobiliary secretion, or both, methods were developed using occlusive balloons. The test segment was perfused with NaCl (2 ml/min, 37 °C) containing [14C]PEG as a nonabsorbable marker, and bicarbonate output was quantitated. Mean (±SE) basal proximal duodenal bicarbonate output was 143 ± 17 μmol/cm · h. A 5-min infusion of 25, 50, and 100 mM HCl directly into the isolated proximal duodenal test segment increased bicarbonate output to 167 ± 29, 199 ± 19, and 278 ± 49 μmol/cm · h, respectively, during the hour after acidification. Distal duodenal acidification (25, 50, and 100 mM) also increased bicarbonate output from the isolated proximal duodenal test segment. A synthetic prostaglandin E1 analogue, misoprostol (1.67–13.3 μg/min), infused directly into proximal or distal test segments significantly stimulated bicarbonate outbreak; peak responses were 644 ± 35 μmol/cm · h and 171 ± 20 μmol/cm · h (p < 0.001), repectively. Thus, in humans, (a) the proximal and distal duodenal mucosa secretes bicarbonate at rest; (b) direct acidification of the proximal duodenum stimulates bicarbonate output; (c) acidification of the distal duodenum beyond the isolated test segment also increased proximal duodenal bicarbonate output; and (d) a synthetic prostaglandin E1 analogue stimulated both proximal and distal bicarbonate output; however, distal duodenal bicarbonate output was significantly less, indicating a proximalto-distal gradient in bicarbonate secretion.

Effect of peptide YY on gastric, pancreatic, and biliary function in humans

The effect of peptide YY (PYY) on gastric and pancreatico-biliary secretion was studied in humans. Peptide YY was infused into groups of 6 healthy volunteers at doses of 0.59, 0.20, and 0.064 pmol · kg−1 · min−1. The two higher doses caused a significant suppression of gastric acid and pepsin output during background stimulation with pentagastrin. The middle dose of PYY (0.20 pmol · kg−1 · min−1) that increased plasma PYY levels by 27 ± 2 pM caused a 90% ± 18% (mean ± SEM; p < 0.001) reduction in the incremental gastric volume response to pentagastrin. Similarly this dose of PYY caused a substantial inhibition of the acid (77% ± 14%; p < 0.005) and pepsin (96% ± 22%; p < 0.01) response to pentagastrin; in 2 subjects, pepsin output fell to below basal levels. In contrast, the highest dose of PYY (0.62 pmol · kg−1 · min−1) had no significant influence on duodenal juice volume, output of bicarbonate, trypsin, or bilirubin during low dose stimulation with secretin (0.25 pmol · kg−1 · min−1) and cholecystokinin-8 (0.15 pmol · kg−1 · min−1). Thus PYY concentrations in the circulation similar to those seen after the ingestion of food cause a marked reduction in gastric secretion. This peptide should therefore be considered as one of the possible candidates for the classical enterogastrone.

Evidence for modulation of motilin secretion by pancreatico-biliary juice in health and in chronic pancreatitis.

The gut hormone motilin can initiate the interdigestive migrating motor complex. There are synchronous cyclic changes in plasma motilin-like immunoreactivity (MLI) levels and pancreatico-biliary secretion during the interdigestive period which may be causally related. The purpose of this study was to investigate the role of pancreatico-biliary secretion into the gut as a modulator of plasma MLI concentrations. In six healthy subjects, the mean basal plasma MLI level was 130 +/- 16 pg/ml. Infusion of cholecystokinin octapeptide (CCK-8) stimulated MLI secretion, with an integrated (30 min) response of 2028 +/- 340 pg/min X ml. Intraduodenal perfusion of pancreatico-biliary juice produced a similar increase in plasma MLI, with a 30 min integrated response of 2190 +/- 270 pg/min X ml. Neither enzyme activity, osmolarity, or pH accounted for the response. In six patients with exocrine pancreatic insufficiency, although their mean basal plasma MLI concentration of 205 +/- 44 pg/ml was significantly higher than that observed in healthy subjects, there was no significant plasma MLI increase after CCK-8 infusion. Pancreatic exocrine secretion was severely compromised in these patients, as evidenced by the markedly reduced peak lipase (3.8 +/- 0.6 kU/h) and trypsin (2.4 +/- 0.5 kU/h) outputs. In contrast, infusion of pancreatico-biliary juice obtained from healthy subjects caused a rise in plasma MLI, with a 60 min integrated response of 3912 +/- 1031 pg/min X ml, which was similar to that of 3947 +/- 472 pg/min X ml in healthy subjects. We conclude that there is an undefined factor in pancreatico-biliary juice that stimulates MLI release. A deficiency of pancreatic exocrine secretion may be responsible for the impaired MLI response to CCK-8 stimulation in chronic pancreatitis. Since MLI is known to initiate the formation of the interdigestive migrating motor complexes, diminished motilin release secondary to pancreatic exocrine deficiency may result in disordered gastrointestinal motor activity in patients with chronic pancreatitis.