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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 × 0.5 mgikg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymo-trypsin 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 4448 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.

Fecal elastase-1 is a candidate for a sensitive noninvasive test detecting chronic pancreatitis. This prospective study enrolled 10 healthy male controls and 23 patients referred for tube testing of pancreatic function. It was designed (a) to correlate duodenal outputs and fecal concentrations of elastase-1 with duodenal outputs of amylase, lipase, trypsin, and chymotrypsin in the fed state (duodenal perfusion of a mixed liquid meal at 2.5 kcal/min for 150 min), (b) to compare the diagnostic accuracy of fecal elastase-1 and fecal chyrnotrypsin, and (c) to characterize the cyclical pattern of postprandial pancreatic secretion in healthy subjects and patients with chronic pancreatitis. Based on their enzyme responses to duodenal meal perfusion and imaging procedures, 12 patients were classified as having normal pancreatic function and 11 patients as having chronic pancreatitis. Duodenal enzyme outputs of elastase-1 were markedly lowered in chronic pancreatitis (p<0.0001) and correlated well with the outputs of the other four enzymes (r>0.71, p<0.00001). Fecal concentrations of elastase-1 were also clearly reduced in chronic pancreatitis (p<0.0001). Fecal chyrnotrypsin was less strongly associated with duodenal enzyme outputs (r0.33 to r0.587), whereas fecal elastase-1 correlated more precisely with the duodenal outputs of all five enzymes (r0.637 to r0.830, p<0.00001). Sensitivity and specificity in the detection of chronic pancreatitis amounted to 0.64 and 0.95 for fecal elastase-1 and 0.27 and 0.95 for fecal chyrnotrypsin, respectively. In the postprandial state, peaks of enzyme secretion occurred at a frequency of about 1 peak/150 min. The amplitude but not the frequency of secretory peaks was markedly reduced in chronic pancreatitis (p<0.01). We conclude that fecal elastase-1 clearly exceeds the sensitivity of fecal chyrnotrypsin in the diagnosis of chronic pancreatitis but does not reliably detect all cases with mild to moderate disease. The pattern of postprandial pancreatic secretion is cyclical, even with minimal secretory outputs in chronic pancreatitis.

In the present study an improved method of reversed-phase high-performance liquid chromatography (HPLC) for separation of rat pancreatic juice proteins is introduced. Aliquots of pancreatic juice were saved from conscious rats during basal secretion. The secretory proteins were separated on a wide-pore silica column by use of a multistep acetonitrile/water gradient. Up to 14 individual peaks could be separated by one run. Molecular weight analysis by sodium dodecyl sulfate (SDS)-gels allowed identification of peaks representing amylase, lipase, procarboxypeptidases, proelastase, chymotrypsinogen, and trypsinogen. Injection of pure rat amylase increased one specific peak which was assumed to represent amylase in the juice profile. Small amounts of residual enzymatic activities were measured for amylase, trypsin, and chymotrypsin in material of certain peaks. Activities of lipase, ribonuclease, and carboxypeptidases were not found, which reflected degradation of these enzymes by the separation procedure. High activities of phospholipase A, were detected in one specific, early-eluting peak. Reversed-phase HPLC offers precise, reproducible, and rapid separation of the major proteins of rat pancreatic juice.

Pancreatic insufficiency was induced in rats by a single injection of 50 μl oleic acid into the pancreatic duct over a period of 3 min. Exocrine tissue was destroyed within 3–6 days, and after 6 weeks the remaining pancreas equaled 2.7 of the original organ. The rats showed retardation of body weight in spite of normal food intake. After 7 weeks the fecal weight increased by 23, and the fecal chymotrypsin activity decreased by 90 compared to controls. At this time plasma cholecystokinin (CCK) concentrations were significantly elevated. The amylase content in the remaining pancreas was reduced by 99, and trypsin content was reduced by 93. Unstimulated protein discharge from the remnant pancreas in vitro was threefold higher compared to secretion from control tissue. Thus a simple, reproducible model for inducing persistent pancreatic insufficiency was developed. To compensate for the loss of exocrine tissue, the remaining acinar cells adapt by a CCK-mediated increase in protein secretion.