Vagal influence on cholecystokinin and neurotensin release in conscious dogs

Cholecystokinin (CCK) release in seven conscious dogs was investigated by means of modified sham feeding. After sham feeding mean CCK concentrations rose from a basal value of 1.0 +/- 0.2 pmol/l to a peak value of 2.4 +/- 0.3 pmol/l (p less than 0.005). The release in response to sham feeding amounted to half of that seen after normal feeding. Atropine significantly altered CCK output after sham feeding (basal, 1.0 +/- 0.2 pmol/l; peak 1.3 +/- 0.3 pmol/l). Sham feeding did not affect neurotensin release. It is concluded that an important cephalic phase of CCK release exists which seems to be dependent on a cholinergic mechanism.     

Role of cholecystokinin in the negative feedback control of pancreatic enzyme secretion in conscious rats

Using a specific radioimmunoassay for cholecystokinin (CCK) we have studied the relation between circulating CCK concentrations and the feedback regulation of pancreatic enzyme secretion in conscious rats. Recirculation of diverted bile-pancreatic juice into the duodenum or intraduodenal perfusion of trypsin during biliary-pancreatic juice diversion produced basal output of amylase and trypsin and low portal CCK levels (less than 10 pmol/L). Biliary-pancreatic juice diversion or inactivation of trypsin caused increased CCK concentrations (peak values 50-100 pmol/L) and enzyme outputs. During biliary-pancreatic juice diversion, infusion of the CCK receptor antagonist proglumide suppressed the enzyme response without altering the increase in CCK. Measurement of portal and peripheral CCK during biliary-pancreatic juice diversion yielded values of 131 +/- 37 and 32 +/- 5 pmol/L, respectively. The peripheral CCK levels corresponded to concentrations achieved during exogenous CCK-8 infusion which resulted in similar enzyme outputs. Gel chromatography of portal plasma during diversion of biliary-pancreatic juice revealed one peak of CCK corresponding to CCK-8, and a larger peak eluted between CCK-33 and CCK-8, probably representing CCK-22. Similar CCK components were found in water extracts of jejunal mucosa, whereas the acetic acid extracts mainly contained CCK-33/39. We conclude that the negative feedback regulation of pancreatic enzyme secretion in rats is mediated by the release of CCK from the intestine and that the major molecular form of CCK in plasma is probably CCK-22.     

Secretin release in coeliac disease. Plasma secretin concentration and bicarbonate output to the duodenum after intraduodenal acid infusion in coeliac patients before and after treatment

Infusion of 40 ml 0.1 mol/l HCl into the duodenum in eight untreated coeliac patients was followed by an increase of the plasma immunoreactive secretin (IRS) concentration from 1.6 +/- 0.2 pmol/l to a peak level of 2.4 +/- 0.3 pmol/l (p less than 0.05). After treatment with a gluten-free diet, the same patients showed an increase from 1.4 +/- 0.3 pmol/l to a peak level of 5.5 +/- 0.9 pmol/l after intraduodenal acid infusion, which was significantly higher than before treatment (p less than 0.01). In control subjects, intraduodenal acid infusion was followed by an increase from 1.4 +/- 0.2 pmol/l to 6.7 +/- 1.1 pmol/l, which was significantly higher than in untreated coeliac disease (p less than 0.01) but did not differ from what was found in treated coeliac patients. Significant differences in pH, volume, or bicarbonate content of the duodenal aspirates or the basal IRS levels were not found.     

Comparative study of the effects of equal amounts of fat, protein, and starch on plasma cholecystokinin in man

The effect of ingestion of 50 g fat, 50 g protein, and 50 g starch on plasma cholecystokinin (CCK) concentrations was studied in eight healthy volunteers. Plasma CCK concentrations were measured by radioimmunoassay with Bolton-Hunter-labelled CCK 33, CCK 33 standard, and antibody T204. Antibody T204 was directed to the sulphated tyrosine region of CCK. Ingestion of fat and protein induced significant increases in plasma CCK, whereas ingestion of starch did not significantly influence plasma CCK levels. Peak increments in plasma CCK after fat (4.8 +/- 0.9 pmol/l) and protein (3.4 +/- 0.5 pmol/l) were significantly greater than that after starch (0.9 +/- 0.3 pmol/l). Similarly, the integrated plasma CCK secretion after fat (213 +/- 49 pmol/l X 120 min) and after protein (178 +/- 53 pmol/l X 120 min) was significantly greater than that found after ingestion of starch (9 +/- 23 pmol/l X 120 min). It is concluded that, in contrast to starch, fat and protein are potent stimuli for the release of CCK.     

Plasma enteroglucagon related to malabsorption in coeliac disease

Plasma enteroglucagon was measured before and during three hours after a standard meal in 21 untreated adult patients with suspected coeliac disease who all had villous atrophy of the small intestinal mucosa and malabsorption, and in nine control subjects. In 11 of these patients the diagnosis of coeliac disease was confirmed and 10 were again investigated on a gluten free diet. The coeliac patients had higher basal (37 +/- 9 pmol/l, mean +/- SE, p less than 0.05) and postprandial (70 +/- 9 pmol/l, p less than 0.005) mean plasma enteroglucagon concentrations than the control subjects (basal 14 +/- 4 pmol/l, postprandial 25 +/- 5 pmol/l). The 10 coeliac patients on gluten free diet for five to 20 months had a basal mean plasma enteroglucagon concentration not significantly lower than before treatment (25 +/- 5 pmol/l) but significantly lower postprandial enteroglucagon concentrations than before treatment (40 +/- 7 pmol/l, p less than 0.025). Postprandial plasma enteroglucagon concentration after 90 minutes in untreated patients correlated positively to the faecal fat excretion (r = 0.58, p less than 0.02). It correlated negatively to the urinary five hour D-xylose excretion after an oral load of 165 mmol D-xylose (r = -0.71, p less than 0.01). Thus, the postprandial plasma enteroglucagon concentrations in untreated coeliac disease were related to the degree of malabsorption and they normalised during treatment with a gluten free diet.     

The effect of the cholecystokinin receptor antagonist MK-329 on meal-stimulated pancreaticobiliary output in humans.

To determine the physiological role of circulating cholecystokinin (CCK), the effect of the CCK receptor antagonist MK-329 on upper digestive processes was investigated in six normal volunteers after a mixed meal. In a double-blind, two-period, randomized crossover design, the subjects received either 10 mg MK-329 or placebo orally 3 hours 15 minutes before the meal, which contained 51CrCl3 as food marker. A five-lumen tube with the tip in the distal duodenum allowed continuous marker infusion (57Co-B12) and duodenal aspiration as well as recordings of antral and duodenal motility patterns via three pressure sensors. Postprandially, MK-329 caused a significant reduction of 30%-60% (P less than 0.05) in pancreatic trypsin output during the initial three 15-minute periods; thereafter, the output was virtually the same than after placebo. Thus, the integrated enzyme response was only reduced by 15% (NS) during the 3-hour period beginning 15 minutes after the meal. In contrast, gallbladder contraction, determined by total bile acid excretion, was inhibited by 77% (P less than 0.05), indicating a crucial role of CCK in regulating gallbladder motility. Except for the initial 30 minutes postprandially, MK-329 also induced a significant reduction in duodenal pH with mean values ranging from 3.5 +/- 0.2 to 4.1 +/- 0.3 compared with 4.5 +/- 0.3 to 5.0 +/- 0.4 after placebo (P less than 0.05), probably because of lowered secretion of pancreatic bicarbonate. Gastric emptying rate was significantly accelerated by MK-329 during the initial 75 minutes after the meal, but the time for 50% emptying did not differ from placebo [127.5 +/- 7.7 vs. 140.0 +/- 9.0 minutes (NS)]. No changes were observed in the motility pattern of the proximal duodenum after feeding. Whereas MK-329 only caused a slight increase of the basal plasma CCK concentrations, the postprandial levels were markedly enhanced. Peak concentrations were 10.0 +/- 1.3 vs. 4.0 +/- 0.5 pmol/L after placebo (P less than 0.001), and the integrated response exceeded the control value by 175% (P less than 0.01). The results suggest that circulating CCK is not an essential mediator of the postprandial pancreatic enzyme secretion in humans, whereas it plays a critical role in gallbladder emptying.     

Fish oil reduces gastric acid secretion.

BACKGROUND: The aim of the present investigation was to study gastric acid secretion and release of gastrin, cholecystokinin (CCK), and secretin during intraduodenal perfusion of either fish oil or trioleate. METHODS: Seven healthy volunteers were stimulated on two separate days in random order with intraduodenal perfusates of either fish oil or trioleate. RESULTS: Intravenous infusion with gastrin-17 was used as a background stimulation in doses mimicking a postprandial situation (39.9 +/- 4.8 pmol/l fish oil and 43.6 +/- 3.8 pmol/l trioleate). Gastric acid secretion increased significantly from a basal level of 0.7 +/- 0.1 meq/15 min to 4.0 +/- 0.6 meq/15 min (P < 0.05) before perfusion of fish oil, which reduced gastric acid secretion to 1.9 +/- 0.4 meq/15 min (P < 0.01). After termination of fish oil perfusion gastric acid secretion increased to preperfusion concentrations (P < 0.01). Perfusion of trioleate did not influence gastric acid secretion. Plasma concentrations of CCK rose significantly during perfusion of fish oil (from 2.8 +/- 0.6 pmol/l to 4.4 +/- 0.7pmol/l, P<0.01), whereas trioleate only tended to increase CCK concentrations. Plasma concentrations of secretin did not change during perfusion of fish oil; however, concentrations were significantly lower during and after perfusion of trioleate (P < 0.01). CONCLUSION: The present study shows that intraduodenal perfusion of fish oil is associated with a significant reduction of the gastric acid secretion stimulated by gastrin in healthy humans.     

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

The effect of vagal stimulation on the release of cholecystokinin in anaesthetized pigs

The effect of electrical vagal stimulation on the release of cholecystokinin (CCK) was studied in nine anaesthetized pigs. Plasma CCK concentrations were measured radioimmunologically by means of an antiserum specific for the sulphated tyrosine region of CCK. Stimulation of both vagal nerves for 10 min induced an increase in CCK concentrations from 1.9 +/- 0.4 pmol/l to a peak value of 3.6 +/- 0.4 pmol/l in portal vein plasma and from 1.5 +/- 0.3 to 2.7 +/- 0.4 pmol/l in arterial plasma. Mean integrated increments during stimulation were 12.0 +/- 2.5 pmol/l/10 min (p less than 0.01) and 8.3 +/- 1.0 pmol/l/10 min (p less than 0.001), respectively. The results suggest a vagal innervation of the CCK cell in the upper small intestine.     

Effect of atropine on the plasma cholecystokinin response to intraduodenal fat in man

The present study was undertaken to determine whether atropine inhibits the plasma cholecystokinin (CCK) response to intraduodenal fat. Plasma CCK concentrations were measured by radioimmunoassay using two sequence-specific antibodies. Antibody 1703 bound to all COOH-terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 was specific for the sulphated tyrosine region of CCK. Intraduodenal instillation of 60 ml corn oil in 6 normal subjects induced significant increases in plasma CCK. Intravenous administration of atropine (0.015 mg/kg as bolus followed by 0.005 mg/kg X h over 3 h) resulted in significant inhibition of plasma CCK concentrations at 10, 20 and 30 min (antibody 1703) and at 20 and 30 min (antibody T204 ) after instillation of fat. However, the peak increments in plasma CCK during atropine (8.6 +/- 1.9 pmol/l, antibody 1703; 5.4 +/- 1.1 pmol/l, antibody T204 ) were not different from those found without atropine (6.3 +/- 0.8 pmol/l, antibody 1703; 3.9 +/- 0.9 pmol/l, antibody T204 ). Similarly, the integrated plasma CCK secretion after intraduodenal fat was not significantly different when measured during atropine (461 +/- 119 pmol/l X 3 h, antibody 1703; 269 +/- 97 pmol/l X 3 h, antibody T204 ) and without atropine (428 +/- 62 pmol/l X 3 h, antibody 1703; 188 +/- 66 pmol/l X 3 h). It is concluded that administration of atropine delays but does not inhibit the CCK response to intraduodenal corn oil in man.     

Thr28, Nle31 CCK-9--an useful CCK analogue in stimulation tests of pancreatic exocrine function

In the present study we examined the effect of Thr28 Nle31-CCK 25-33 (CCK-9) on pancreatic exocrine function in man. In subjects without pancreatic disease CCK-9 together with i.v. secretin (0.5 CU/kg/h) elicited a maximal stimulation of amylase output at a dose of 10 pmol/kg/h while trypsin and chymotrypsin were stimulated maximally at a dose of 30 pmol/kg/h. Higher doses of 60 and 100 pmol/kg/h had no additional effects. Lipase secretion was stimulated by secretin alone with no additional effect of CCK-9. During all doses of CCK-9 no side effects were observed. In patients with chronic pancreatitis a dose of 30 pmol/kg/h was also sufficient to obtain maximal enzyme output. In conclusion this derivative of CCK can be considered as a potent and useful alternative to amphibian caerulein in direct pancreatic function tests.     

Somatostatin, insulin and glucagon after arginine stimulation in active and treated acromegaly

Ten acromegalic patients, 28-71 years old, were compared with 10 normal controls, 21-39 years old. In another study, 7 patients with active acromegaly, 19-70 years old, were investigated before and 4-9 months following transsphenoidal adenectomy and radiation. They were all investigated following an arginine infusion (0.5 g/kg/20 min). Although the mean plasma somatostatin (somatotrophin release inhibiting factor (SRIF] was somewhat higher in acromegalic patients compared to normal controls (mean basal values 21 +/- 3.8 and 16.6 +/- 2.1 pmol/l, respectively), the difference was not significant. The patients had higher serum insulin (peak values 118 +/- 23.9 and 63 +/- 11.8 mU/l, respectively) and lower plasma glucagon (peak values 171 +/- 29.0 and 310 +/- 52.7 pmol/l, respectively). Plasma SRIF increased during arginine infusion, but the concentrations were similar before and following the operation (mean basal values 18.2 +/- 2.6 and 15.2 +/- 2.3 pmol/l, respectively). Serum insulin was significantly higher before the operation (peak values 154 +/- 38.8 and 91 +/- 24.9 mU/l, respectively). Plasma glucagon was similar before and after the operation (peak values 143 +/- 23.4 and 127 +/- 22.7 pmol/l, respectively). Plasma SRIF is similar in active acromegaly and normal controls, and in acromegaly before and following treatment, despite differences in serum growth hormone (GH), serum insulin and plasma glucagon. This points towards a modulating role for GH on plasma SRIF, possibly by affecting the other islet cell hormones.     

Effect of CCK on food intake in man: physiological or pharmacological effect?

The present study was designed to determine in humans the dose of CCK which suppresses food intake. 18 male subjects received in randomized order either i.v. saline or Thr28 Nle31 CCK 25-33 (CCK-9) at 100 or 500 pmol/kgh, respectively. In addition, 7 subjects received CCK together with the opiate receptor antagonist naloxone to examine if activation of endogenous opioids might interfere with the potential satiating effect of CCK. Food intake during saline was 32 +/- 2 sandwiches (mean +/- SEM), during CCK-9 100 pmol/kgh 28 +/- 2 (n.s.) and only 12 +/- 3 during CCK-9 500 pmol/kgh (p less than 0.01). The respective water intake was 730 +/- 70 ml, 590 +/- 60 ml (n.s.) and 320 +/- 50 ml (p less than 0.01). Naloxone further reduced food and water intake during high but not low dose CCK or saline. During saline postprandial insulin levels rose by 49 +/- 6 microU/ml within 45 min which was attenuated during low dose (23 +/- 6 microU/ml; p less than 0.01) and high dose CCK-9 (1 +/- 1 microU/ml; p less than 0.001). Plasma glucagon did not change in control or CCK experiments. The postprandial rise of pancreatic polypeptide was attenuated during high dose CCK. Naloxone had no effect on the hormonal response except for a prolonged reduction of insulin and glucose levels following high dose CCK + naloxone. Plasma CCK levels rose by 5.4 pmol/l in controls but by 55 and 255 pmol/l during the low and high dose CCK infusion, respectively. These data demonstrate that suppression of food intake in man by i.v. CCK is a pharmacological rather than a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cholecystokinin-stimulated peak lipase concentration in duodenal drainage fluid: a new pancreatic function test

OBJECTIVE: Hormonal stimulation with secretin or cholecystokinin (CCK) is the most sensitive means of assessing pancreatic function. Secretin is not available, and current CCK tests are cumbersome, requiring dual tube intubation and marker perfusion techniques. The aim of this study was to test the efficacy of a new CCK-stimulated pancreatic function test measuring peak lipase concentration. METHODS: A Dreiling gastroduodenal tube was inserted to the ligament of Treitz, and fluid was collected on ice for 80 min in four 20-min aliquots. CCK was infused i.v. at a constant rate of 40 ng/kg/h. Gastric aspirations were discarded. Duodenal aspirates were analyzed for volume and enzyme concentration with a clinical laboratory autoanalyzer. RESULTS: Nineteen healthy volunteers and 18 chronic pancreatitis patients were studied. Lipase concentration and secretory volume showed a peak response by 40 min of stimulation, whereas amylase response was variable. The mean peak lipase concentrations (+/-SEM) for normal volunteers and mild, moderate, and advanced chronic pancreatitis patients were 16.9+/-1.9, 7.9+/-1.7, 3.7+/-1.2, and 2.1+/-0.6 x 10 5 IU/L, respectively. Lower peak lipase concentrations were significantly associated with more advanced chronic pancreatitis (p < 0.001). The receiver operating characteristic curve area for all chronic pancreatitis patients was 0.944 (95% CI = 0.825-0.985). A peak lipase concentration of 780,000 IU/L provided a sensitivity and specificity of 0.833 and 0.867, respectively. This CCK test was well tolerated and without complications. CONCLUSIONS: Lipase concentration in duodenal fluid increases nearly 3-fold from baseline after CCK stimulation in healthy volunteers but is markedly reduced in patients with chronic pancreatic disease. Peak lipase concentration is a significant predictor of chronic pancreatitis and correlates with severity of pancreatic disease. Aspiration of duodenal drainage fluid with a Dreiling tube and analysis with a laboratory autoanalyzer are less cumbersome than marker perfusion and back titration techniques. Measurement of enzyme concentration instead of output could lead to the development of an endoscopic or through-the-scope screening method for assessing patients with suspected chronic pancreatitis or chronic abdominal pain.     

Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.     

Gastric lipase in alcoholic pancreatitis. Comparison of secretive profiles following pentagastrin stimulation in normal adults and patients with pancreatic insufficiency

The aims of this study were to evaluate the amount of gastric lipase secreted by the stomach in normal adults and to elucidate a possible adaptative secretion of this enzyme in response to pancreatic insufficiency secondary to alcoholic chronic pancreatitis. Forty-one subjects underwent a gastric intubation. Pentagastrin (6 micrograms.kg-1.h-1 IV) significantly increased gastric lipase concentration and output. Stimulated gastric lipase output in seven normal subjects was 12,598 +/- 2036 U/h (by using tributyrin as substrate). Outputs where higher (P less than 0.02) in 17 patients with pancreatic insufficiency who were not drinking alcohol, but were not significantly different in nine patients who continued to drink (20,413 +/- 1778 U/h and 21,953 +/- 4973 U/h, respectively). On the other hand, high gastric lipase outputs were found in eight patients with duodenal ulcers and no evidence of pancreatic dysfunction (23,180 +/- 262 U/h). The time required to reach maximal lipase output (peak output) following pentagastrin stimulation was the same in all groups (approximately 38 minutes) except for the group of patients with pancreatic insufficiency who did not drink alcohol, in whom it was significantly reduced (approximately 26.5 minutes). Secretory patterns of gastric lipase and pepsin were closely comparable. Gastric lipase secretion could be increased in several clinical conditions and particularly in patients with pancreatic insufficiency caused by alcoholic chronic pancreatitis who have been abstinent for a long time.     

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.     

Impaired pancreatic polypeptide release in chronic pancreatitis with steatorrhoea.

Pancreatic polypeptide (PP) is a newly discovered hormonal peptide localised in a distinct endocrine cell type in the pancreas. PP circulates in plasma and in normal subjects levels rise substantially on the ingestion of food (mean rise 138 pmol/l). In 10 patients with chronic pancreatitis with exocrine deficiency the PP response to a test breakfast was greatly reduced (mean rise 20 pmol/l, P less than 0.001). PP response to the meal was normal in 10 patients with active coeliac disease and 12 patients with acute tropical sprue with steatorrhoea.     

Role of cholecystokinin in cholestyramine-induced changes of the exocrine pancreas

This study was an investigation of the role of cholecystokinin (CCK) in the stimulatory action of cholestyramine on rat exocrine pancreas. Postprandial CCK release was significantly enhanced by acute administration of cholestyramine (12.7 +/- 1.8 vs 3.7 +/- 0.5 pmol/L in controls). Over four weeks, rats were fed either regular diet or diet containing 6% cholestyramine, and were treated with the specific CCK receptor antagonist L-364,718 (2 x 0.5 mg/kg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymotrypsin contents. L-364,718 abolished these effects. Concomitant administration of antagonist and cholestyramine elevated amylase content, compared to controls. CCK levels in fasted animals did not differ between the four groups. The effect of the same dose of L-364,718 on pancreatic enzyme depletion, induced by the protease inhibitor camostate, was studied in a control experiment. A single dose of camostate (200 mg/kg) caused a 44-68% decrease in enzyme content. L-364,718 reversed this effect for all enzymes. We conclude that CCK is the mediator of cholestyramine-induced pancreatic hypertrophy and increase in content of proteases. After long-term administration, the CCK receptor antagonist, in combination with cholestyramine revealed an agonistic effect on individual, pancreatic enzyme content.     

Effect of a cholecystokinin antagonist on meal-stimulated insulin and pancreatic polypeptide release in humans

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.