Cephalic phase of lipolysis is impaired in pancreatic insufficiency: role of gastric lipase.

BACKGROUND: Gastric lipase contributes significantly to overall lipolysis and is regulated by interacting neuro-hormonal mechanisms. Patients with alcoholic chronic pancreatitis (ACP) have low, or even absent, activity of pancreatic lipases. In that state the secretion of gastric lipase could be essential and compensate for the pancreatic defect. However, conflicting studies have not resolved the order of magnitude of gastric lipase secretion in these patients. This could be explained by differences in regulatory mechanisms, gastric mucosal changes, and abdominal vagal tone. METHODS: Nasogastric intubation with modified sham feeding and upper endoscopy including biopsies for histologic classification and Helicobacter pylori infection status were performed in eight ACP patients, and eight healthy volunteers were studied on separate occasions. Vagal nerve function was assessed by calculation of heart rate variability in ACP patients. Gastric lipase was measured in aspirates by means of enzyme-linked immunosorbent assay and an enzyme kinetic assay. Plasma concentrations of gastrin, secretin, cholecystokinin, and pancreatic polypeptide were measured throughout the study. RESULTS: Sham feeding rapidly and significantly increased gastric lipase secretion in healthy volunteers, whereas ACP patients did not respond to sham feeding. Two of eight patients were infected with H. pylori and had mucosal changes accordingly. The lack of lipase response could not be ascribed to dysfunction of the abdominal vagus. CONCLUSIONS: The cephalic phase of gastric lipase secretion is impaired in ACP patients. Although their fundic cells continue to secrete gastric lipase, they are not subject to normal neuro-hormonal regulation.

Inhibition of human gastric lipase by intraduodenal fat involves glucagon-like peptide-1 and cholecystokinin.

Seven healthy volunteers were intubated with two double lumen nasogastric tubes, one in the stomach, the other in the duodenum. This system allows simultaneous sampling of gastric juice and separate intraduodenal perfusion with a dietary fat (fish oil, 1269 kJ). Gastrin-17 was infused i.v. at a rate of 40 pmol/kg/h throughout the study. Gastric lipase was measured at 15-min intervals as activity (tributyrin) and as immunoreactivity (ELISA). Infusion of gastrin-17 resulted in a stable increase in the plasma concentration from a basal concentration of 8.3 +/- 0.8 pmol/l to 41.4 +/- 4.2 pmol/l. Perfusion with fat reduced gastric lipase activity from 24.2 +/- 5.3 to 7.2 +/- 2.5 kU/l (P < 0.05), and immunoreactivity from 0.7 +/- 0.1 to 0.42 +/- 0.1 mg/l (P < 0.05). After termination of fat perfusion, gastric lipase secretion increased again, though not reaching preinhibitory concentrations. During the intraduodenal perfusion with fat the plasma concentrations of glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) increased from 6.9 +/- 0.5 to 15.1 +/- 1.5 pmol/l (P < 0.05) and from 1.2 +/- 0.4 to 3.8 +/- 0.9 pmol/l (P < 0.05). This study reveals a negative effect of fat in the duodenum on gastric lipase secretion. This effect may be mediated by GLP-1 and/or CCK.

Pancreatic growth after pancreatico-biliary diversion does not increase the capacity to secrete amylase.

BACKGROUND/AIM: Cholecystokinin (CCK) stimulates secretion and evokes a hyperplastic response in the rat pancreas. The aims of this study were to measure the effect of chronic hyperCCKemia induced by pancreatico-biliary diversion (PBD) on pancreatic enzyme concentrations, on amylase secretion by dispersed acinar cells, and on the CCK-stimulated secretion of pancreatic juice in PBD-operated rats. MATERIAL AND METHODS: Forty-five Sprague-Dawley male rats had either PBD or sham operation 4 weeks before sacrifice or additional experiments. In the first study, 25 rats (13 PBD and 12 sham-operated rats) were either freely fed or fasted overnight before sacrifice. The pancreas was dissected out, weighed and analyzed. In the second study, the rats (6 PBD and 7 sham-operated rats) were fasted overnight before pancreatic acini were prepared. Secretion of amylase during stimulation of acini with CCK-8S and carbachol was measured. In the third study (5 sham-operated and 4 PBD rats), the rats were fasted overnight before basal and CCK-stimulated secretion was measured in vivo. RESULTS: PBD-operated rats showed a threefold increase in pancreatic wet weight with increased contents of DNA, protein and water. The concentration of pancreatic amylase was 7-12% of that found in control animals. The concentrations of trypsin and lipase were also lowered. Stimulation of dispersed pancreatic acini with CCK-8S or carbachol resulted in secretion of amylase to a similar extent in PBD and sham-operated rats. There was no difference in the secretion of pancreatic juice in response to CCK, but although the output of amylase from PBD-operated rats increased with CCK, it remained at a low level throughout the study period. CONCLUSION: PBD evoked hyperplastic changes in the rat pancreas and decreased the concentrations of amylase, trypsin and lipase. However, the capacity of acinar cells to secrete amylase remained intact. The stimulated pancreatic secretion was not changed in volume, but the output of amylase was low in PBD-operated rats. The findings are consistent with the idea that the enlargement of the pancreas following PBD does not improve the secretory capacity.

Secretin and gastric lipase secretion.

BACKGROUND: Gastric lipase secretion is stimulated by gastrin in plasma, but its regulation by secretin is unknown. METHODS: In 7 normal persons we investigated the effect of exogenous secretin on the output of gastric lipase stimulated by intravenous gastrin-17. The gastric content was measured using a nasogastric tube for aspiration. The quantitative lipase secretion was measured by an enzyme-linked immunosorbant assay (ELISA) and the lipolytic activity by a kinetic assay. Plasma concentrations of secretin and gastrin were measured by radioimmunoassay. RESULTS: Gastric lipase secretion (the quantity as well as the lipolytic activity) was significantly stimulated by gastrin. In response to secretin infusion, the lipolytic activity increased as acid secretion decreased. CONCLUSION: Secretin in postprandial concentrations does not influence the quantitative gastric lipase secretion stimulated by gastrin, but it increases lipolytic activity due to inhibition of acid secretion.

Nutritional state, growth rate, and morphology after total gastrectomy with restoration of duodenal passage or Roux-en-Y oesophagojejunostomy with or without a pouch: an experimental study in pigs.

OBJECTIVE: To compare the effect of restoration of duodenal continuity by a Roux-en-Y oesophagojejunostomy with or without a pouch on nutritional state, growth, and morphology after total gastrectomy in pigs. DESIGN: Experimental study. SETTING: Teaching hospital, Sweden. MATERIAL: 60 Swedish domestic pigs. INTERVENTIONS: 54 pigs underwent total gastrectomy and 6 had sham operations. 20 pigs had reconstruction by a Roux-en-Y oesophagojejunostomy, 21 had a jejunal loop interposed between the oesophagus and the duodenum, as 13 had a oesophagojejunostomy with jejunal pouch on a Roux-en-Y loop. MAIN OUTCOME MEASURES: Weight, laboratory indicators of nutritional state, and histological appearance of the gut. RESULTS: Growth was significantly retarded in those pigs that had had gastrectomies (p < 0.001) but there were no differences among the experimental groups. Haemoglobin, albumin, and calcium concentrations were significantly lower in the experimental groups than in the control group (p=0.006, 0.02, and 0.002, respectively). Histological examination showed subtotal villous atrophy in the experimental groups, most obvious in the pouch group. Colonic mucosal height was reduced in the experimental groups. CONCLUSION: This study failed to show any advantage in growth rate when restoration of duodenal continuity or a small bowel pouch were compared with a conventional Roux-en-Y oesophagojejunostomy after total gastrectomy. However, restored duodenal passage seemed to benefit calcium homeostasis.

Inhibition of human gastric lipase secretion by glucagon-like peptide-1.

Glucagon-like peptide-1 (GLP-1) may be one of the enterogastrone hormones of the ileal brake mechanism. We therefore studied its effects on gastric lipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. The intestinal incretin hormone GLP-1 (glucagon-like peptide-1, 7-36 amide) was investigated because of its inhibitory effects on gastric acid secretion and motility. GLP-1 infused intravenously in amounts corresponding to the postprandial release significantly inhibited pentagastrin-stimulated gastric lipase secretion and lipolytic activity. The inhibitory effect of GLP-1 persisted in vagotomized patients, suggesting that fundic chief cells, from which gastric lipase is released, or neighboring inhibitory cells could be equipped with GLP-1 receptors. Vagotomized patients had significantly higher plasma concentrations of gastrin and secretin. No significant changes of gastrin, secretin, and CCK secretion were seen during GLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthy volunteers. GLP-1 seems to be a naturally occurring inhibitor of gastric lipase secretion acting via a nonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonal stimulatory as well as inhibitory mechanisms.

Effect of sham feeding and acute suppression of acid secretion on human gastric lipase secretion.

OBJECTIVE: Gastric lipase and gastric acid are secreted simultaneously. The aim of this study was to investigate whether the acid interferes with the lipase secretion. The secretion of human gastric lipase was studied during blockade of gastric acid secretion and modified sham feeding to estimate the impact of these conditions on both gastric lipase enzyme activity and immunoreactivity. METHODS: Eight healthy volunteers were intubated with a nasogastric tube. We examined gastric aspirates for the amount and activity of lipase secretion during basal conditions, after blockade of acid secretion with a proton pump inhibitor (omeprazole iv. infusion), and in response to sham feeding (chewing gum) during the blockade. RESULTS: The amount of secreted gastric lipase was unaffected by blockade of acid secretion and increased significantly after sham feeding (169.9+/-35.7 microg/15 min to 348.1+/-79.2 microg/15 min; p < 0.01). Likewise, the output of enzyme activity increased after sham feeding (0.63+/-0.09 kU/15 min to 1.52+/-0.36 kU/15 min; p < 0.03). The concentration of enzyme activity remained unchanged by blockade of acid secretion, whereas the output of enzyme activity was decreased, probably because of reduced volume secretion or denaturation and conformational changes of the enzyme. Plasma concentrations of gastrin increased in response to blockade of acid secretion (basal 9.6+/-1.4 pmol/L to 13.3+/-2.9 pmol/L; p < 0.02). CONCLUSIONS: Gastric acid secretion is not a prerequisite for gastric lipase secretion. Lipase enzyme activity, though, is sensitive to anacidic conditions.

Total parenteral nutrition influences both endocrine and exocrine function of rat pancreas.

The aim of this study was to examine the effect of total parenteral nutrition (TPN) on the endocrine and exocine function of the pancreas. Endocrine function was investigated using an intravenous glucose tolerance test (IGTT) in rats with TPN for 7 or 14 days. Exocrine function was evaluated by measuring amylase secretion from isolated acini as well as pancreatic weight, water content, protein, and enzymes after 7 days of TPN. When the TPN rats were compared with the controls, the glucose tolerance curve after an IGTT was unchanged, the basal plasma insulin levels were slightly lower and the insulin secretory response to intravenous glucose was markedly impaired. No differences could be seen between the insulin response after 7 days and that after 14 days of TPN. The weight of pancreas, the total content and concentration of pancreatic protein, and the total amylase content of the pancreas were lower, whereas the total content of both chymotrypsin and trypsin was higher. The concentration of DNA remained intact, whereas the total DNA content decreased. The levels of lipolytic enzymes, except for carboxylesterlipase, were unaffected. After TPN treatment, the insulin secretory response to glucose is impaired, the exocrine pancreas is hypoplastic and the storage pattern of pancreatic exocrine enzymes is altered.

Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes.

The activity of pancreatic enzymes declines during aboral intestinal transit. We tested the hypothesis that survival of pancreatic enzyme activities during intestinal transit is affected by amounts or concentrations of calories, nutrients, bile acids, or pancreatic enzymes entering the segments of the small intestine. An oroileal tube was placed in 26 healthy humans. The tube had duodenal, jejunal, and ileal infusion ports for nonabsorbable markers and aspiration ports in the distal duodenum, distal jejunum, and distal ileum. Four infusates of different proportions of protein, fat, and carbohydrate were infused continuously into the duodenum at 40, 90, and 160 kcal/h. Of the nutrients infused into the proximal duodenum, 21 +/- 3, 51 +/- 7, and 39 +/- 5% of fat, protein, and carbohydrate, respectively, were delivered to the distal duodenum. During duodenoileal transit, lipase, chymotrypsin, amylase, and trypsin lost 71 +/- 5, 63 +/- 5, 43 +/- 7, and 38 +/- 9% of activity, respectively (P < 0.01 vs. distal duodenum). During duodenojejunal transit, the activity of each enzyme decreased more than 35% (P < 0.01 vs. distal duodenum), and infusion of more calories into the duodenum improved survival of all enzymes except trypsin (P < 0.05). During jejunoileal transit, greater amounts and concentrations of calories and carbohydrate improved survival of only lipolytic activity (P < 0.01, P < 0.05, respectively), and loss of lipolytic activity correlated directly with delivery of bile acids (r = 0.56, P = 0.05) and chymotrypsin (r = 0.80, P = 0.001) to the distal jejunum. We conclude that intraluminal nutrients increase survival of enzyme activities in the proximal intestine. After absorption of nutrients, the action of chymotrypsin and bile acids decrease lipolytic activity more than activity of other enzymes.

Gastric lipase secretion after sham feeding and cholinergic blockade.

Our purpose was to examine gastric lipase secretion after cephalic stimulation (sham feeding) and to examine the effect of cholinergic blockade. Eight healthy volunteers, four women and four men, age 21-58 years, were studied twice on separate days. They were sham fed with and without infusion of atropine. Gastric content was measured and the amount as well as the activity of gastric lipase output were determined. Plasma concentrations of gastrin, secretin, and cholecystokinin (CCK) were measured simultaneously by radioimmunoassays. Cephalic stimuli can evoke human gastric lipase secretion, and this effect was almost ablated by atropine blockade of cholinergic receptors. The concentrations of CCK and secretin in plasma were unaffected by sham feeding with or without atropine blockade, whereas gastrin was stimulated by sham feeding after atropine blockade. Gastric lipase secretion in man is apparently controlled by interacting vagal and hormonal mechanisms.

Biliodigestive shunt evokes hyperCCKemia and trophic effects in the rat pancreas, but not in the liver or gastrointestinal tract.

The influence of bile on the release of cholecystokinin (CCK) and, thereby, on the regulation of exocrine pancreatic function and growth is unsettled. The aim of this study was to elucidate the effect of long-term diversion of bile from the upper small intestine of CCK release and on the pancreas, liver, and gastrointestinal tract. A surgical biliodigestive shunt was performed in rats, diverting the bile flow directly to the middle of the small intestine. The animals were killed after 4 or 12 weeks. Plasma CCK and trophic effects on the pancreas, liver, and gastrointestinal tract were determined, as were the trypsin and chymotrypsin contents in the intestine. The CCK concentration in plasma increased 10-fold at both time points studied. The pancreas doubled its weight from 4 weeks onward. Also, pancreatic protein, DNA, and amylase contents were increased throughout the study. The liver and gastrointestinal tract were unaffected. Intraluminal bile plays a role in the feedback regulation of CCK release and is involved in this way in the control of pancreatic growth but has no similar effects on the liver or gastrointestinal tract.

Total parenteral nutrition affects the tropic effect of cholecystokinin on the exocrine pancreas.

BACKGROUND: Cholecystokinin (CCK) exerts trophic effects on the exocrine pancreas. Total parenteral nutrition (TPN) results in hypotrophy of the pancreas. The present study aimed to examine the effect of exogenous and endogenous CCK during TPN. METHODS: Seventy-two Sprague-Dawley rats were orally fed or given TPN after pancreaticobiliary diversion (PBD) and were infused with CCK-8S or the CCK-receptor antagonist devazepide for 7 days. RESULTS: Infusion of CCK and PBD caused hyperCCKemia, whereas TPN did not influence the concentration of plasma CCK. The reduced pancreatic contents during TPN could be reversed by CCK but not by PBD. The hyperplastic response to CCK in orally fed rats was abolished during TPN. Devazepide did not influence the pancreatic variables in orally fed and TPN-treated rats. CONCLUSION: TPN reduces the hyperplastic response of the exocrine pancreas to CCK, and CCK reverses the hypotrophy seen during TPN. The effects of CCK on the exocrine pancreas seems to need enteral nutrition for the full expression.

Carboxyl ester lipase (bile salt-stimulated lipase), colipase, lipase, and phospholipase A2 levels in pancreatic enzyme supplements.

BACKGROUND: Pancreatic lipolytic activity originates from lipase (LIP) and its cofactor colipase (COL), carboxyl ester lipase (CEL), and phospholipase A2 (PLA2). Yet there are few data on the levels of individual lipolytic enzymes in pancreatic enzyme supplements (PES). This study determines activity and immunoreactive mass in some commonly used PES and thus contributes to the understanding of the poor relationship between 'lipase dose' and clinical improvements. METHODS: Recommended doses of each PES were incubated at 37 degrees C for 2 h in a 1-mM Tris-maleate buffer, pH 7.0, containing 150 mM NaCl and 1 mM CaCl2. Aliquots for determinations of enzyme activities and for immunochemical mass were taken every half hour. For comparison a standard dose was defined as 10,000 declared lipase units. RESULTS: No simple parallelism between LIP, COL, CEL, and/or PLA2 activities was seen. The LIP contents ranged from 135% to 301% of the standard dose. None of the PES were short of COL (227%-504%). The variation in CEL was twentyfold, and in PLA2 sevenfold. Less variations were seen in the mass composition. There was considerable variation in activity to mass ratios (particularly for CEL), declared lipase units per recommended dose (6000-160,000), and cost (0.36-3.52 SEK). CONCLUSIONS: PES differ considerably in their content of lipolytic enzymes. CEL activities were relatively low and COL and PLA2 activities high compared with normal duodenal content. The manufacturing procedure can be improved to increase the lipolytic activity in PES in a broader meaning. It seems to be most important to increase the amount of CEL. From these in vitro data we advocate a more careful decision in the choice of PES for each patient, depending on the total clinical picture. Money can be saved without disadvantage to the patient.

Deficient gastric lipase secretion in pancreatic insufficiency.

BACKGROUND: Gastrin is an important stimulator of gastric lipase secretion in man. In advanced pancreatic insufficiency gastric lipases might compensate for the lack of pancreatic lipases, but the role of gastrin in such compensation remains to be evaluated. The aim of this study was to examine the effect of gastrin on the gastric lipase secretion in patients with pancreatic insufficiency. METHODS: Eight patients with pancreatic insufficiency secondary to alcohol abuse were studied, and six healthy subjects volunteered as controls for the study. All volunteers received identical doses of intravenous gastrin-17 (10, 30, and 60 pmol/kg/h). The gastric content was measured, using a nasogastric tube for aspiration, and the amount and activity of gastric lipase output were determined. Plasma concentrations of gastrin, secretin, and cholecystokinin were measured by radioimmunoassays. RESULTS: The increased plasma levels of gastrin were accompanied by a dose-dependent increase in the amount and activity of gastric lipase in controls, but in the patients the response was almost abolished. CONCLUSIONS: Gastrin in postprandial concentrations does not influence the secretion of gastric lipase in patients with pancreatic insufficiency due to chronic pancreatitis.

The effect of selective sympathetic denervation on pancreatic exocrine secretion.

The purpose of this study was to investigate the influence of selective sympathetic denervation of the rat pancreas on exocrine secretion and to study whether the observed effects were due to pancreatic trophism. Sprague-Dawley rats were divided into two groups. One group underwent selective sympathetic denervation by skeletonizing the superior and inferior pancreaticoduodenal and splenic arteries. The other group underwent simple laparotomy and served as controls. One week after the operation a catheter was introduced into the bile-pancreatic duct and pancreatic juice was collected at 30-min intervals for 4 h. The output of bicarbonate, total protein, amylase, trypsin, chymotrypsin, lipase, colipase and carboxyesterlipase were determined. Following denervation secretion of pancreatic enzymes was significantly enhanced compared with sham-operated animals. We did not find any signs of pancreatic trophism 1 week after denervation.

What is the best biochemical test to diagnose acute pancreatitis? A prospective clinical study.

OBJECTIVE: To determine which biochemical test is best to distinguish acute pancreatitis from other pancreatic and nonpancreatic diseases associated with hyperamylasemia. DESIGN: We conducted a prospective clinical study of 836 consecutive patients who had a total serum amylase test requested by a physician during a 7-month period. MATERIAL AND METHODS: Radioimmunoassay and enzymatic activity methods were used to measure pancreas-specific proteins of varied size, charge, and stability. In addition, scoring systems were used for the diagnosis of pancreatitis, and statistical analyses were done to determine sensitivity and specificity. RESULTS: We found minor differences in sensitivity and specificity for diagnosis of acute pancreatitis among pancreatic isoamylase, phospholipase A2, colipase, lipase, and carboxylester lipase. Of these tests, the combination of isoamylase and phospholipase A2 had a small but statistically significant increased sensitivity (90%; 95% confidence interval [CI] = 74 to 98%) and specificity (93%; 95% CI = 91 to 95%) over isoamylase (90% and 92%, respectively; 95% CI = 90 to 94%) and phospholipase A2 (90% and 75%, respectively; 95% CI = 72 to 78%) alone for the diagnosis of acute pancreatitis. CONCLUSION: Pancreas-specific proteins are satisfactory for diagnosing acute pancreatitis if the test is validated by the laboratory. Clinically, the slight advantage of using both isoamylase and phospholipase A2 does not outweigh the expense of performing two assays; we recommend using isoamylase to diagnose acute pancreatitis.

Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences.

The alkaline sphingomyelinase (SMase) was first found in rat intestinal brush border. The important roles of this enzyme in digestion of sphingomyelin and in mucosal cell proliferation have been suggested. In the present work, the distribution of the alkaline SMase in the tissues of human beings and animals have been studied. By assaying the enzyme activity in human biopsy samples, we found that the alkaline SMase activity was absent in the stomach, increased in the duodenum, present at high levels in the small intestine, and slightly declined in the colon and rectum. High activities were found similarly in the intestinal contents of the healthy adults and infants. The activities were also found in the intestinal mucosa of rats, normal and germ-free mice, and hamsters with the same distribution pattern as in humans, but not in the intestinal mucosa of guinea pigs. Apart from the intestinal tract, a SMase activity preferring alkaline pH was identified in human and guinea pig bile, but not in the bile of rat, pig, sheep, and cow. No activity was found in either pancreatic tissue or pancreatic juice in all species tested, and none was detected in human urine and milk. In conclusion, alkaline SMase exists predominantly in the digestive system with considerable tissue and species differences.

In vitro effects of ethanol on human gastric and pancreatic lipolytic activities/enzymes.

BACKGROUND: Ethanol ingestion may disturb fat digestion and absorption by affecting gastric, intestinal, hepatic, and pancreatic functions. Involved mechanisms are not well understood. We examined in vitro ethanol effects on gastric and pancreatic lipolytic activity. METHODS: Human gastric juice, pure gastric lipase, pancreatic lipase, colipase, carboxyl ester lipase, phospholipase A2, and duodenal contents were a) preincubated at 37 degrees C with ethanol (0-30%) and then assayed under normal conditions (pH-stat titration), or b) assayed in the presence of various ethanol concentrations (0-30%). RESULTS: Ethanol reduced gastric and pancreatic lipolytic activities in a dose-dependent manner. The effect was more pronounced with alcohol present in the assay medium, with 5% ethanol reducing carboxyl ester lipase activity by 10%, gastric lipase activity by 20%, and pancreatic lipase activity by 46%. Colipase and phospholipase A2 activities were only slightly affected by ethanol. CONCLUSIONS: Observed effects of ethanol on gastric and pancreatic lipase may be important when fat digestion is already impaired due to gastric, intestinal hepatic, and/or pancreatic diseases.

Time-course of the pancreatic changes following long-term stimulation or inhibition of the CCK-A receptor.

Cholecystokinin (CCK) reportedly induces both hyperplastic and hypertrophic changes in the pancreas. Blockade of the CCK receptor results in decreased pancreatic secretion and atrophy. The aim of this study was to evaluate the time-course of the effects of stimulation and inhibition of the CCK-A receptor in the rat exocrine pancreas. Male rats had infusion of sulfated CCK-8, the CCK-A receptor antagonist devazepide, or sodium chloride by osmotic minipumps. After 36 h, 3, 7, or 28 d the rats had ip injections of thymidine, and 1 h later they were sacrificed. The pancreas was excised, weighed, and its content of protein, DNA, water, and enzymes was analyzed. Histologic samples were prepared for autoradiography. Pancreatic weight, protein, and DNA were increased at 36 h after the start of CCK infusion and throughout the study period. CCK stimulation also increased the content of trypsin at days 3 and 28. The labeling index of pancreatic acinar cells was increased at 36 h. Blockade of endogenous CCK by the receptor antagonist devazepide led to decreased pancreatic weight from the third day of infusion, whereas the protein content was decreased from the seventh day. At day 28, the DNA content was decreased by devazepide. However, the labeling index of acinar cells decreased transiently already at 36 h. Neither CCK nor devazepide caused any changes of protein content:DNA content ratio during the study. Continuous infusion of CCK caused pancreatic hyperplasia already after 36 h. Stimulation up to 28 d did not cause any further effects. The adverse changes found after blockade of the CCK-A receptor showed much of the same time-course.