cholecystokinin and Choline-Deficiency

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.

Topics: Acute Disease; Amylases; Animals; Bile Acids and Salts; Ceruletide; Cholecystokinin; Cholestyramine Resin; Choline Deficiency; Feedback; Female; Mice; Pancreatitis; Taurocholic Acid

The effects of the cholecystokinin receptor antagonist L-364,718 was studied in a model of mild pancreatitis induced in mice by repeated injections of the secretagogue caerulein and in a lethal form of pancreatitis induced by feeding mice an ethionine-supplemented choline-deficient diet. L-364,718 prevented the caerulein-induced rise in serum amylase and pancreatic weight in a dose-dependent manner, the most effective dose being 0.1 mg/kg body wt. L-364,718 also prevented the caerulein-induced pancreatic inflammation as seen by light microscopy. L-364,718 offered no protective effects as determined by changes in serum amylase, pancreatic weight, histology, or mortality in the ethionine-supplemented choline-deficient diet model.

Topics: Amylases; Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Choline Deficiency; Devazepide; Ethionine; Male; Mice; Organ Size; Pancreas; Pancreatitis; Receptors, Cholecystokinin

The effects of a potent cholecystokinin (CCK) receptor antagonist, L-364,718, on two forms of experimental acute pancreatitis in mice were evaluated. The antagonist prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that followed administration of a supramaximally stimulating dose of the cholecystokinin analogue cerulein. In contrast, the same dose of L-364,718 (1 mg/kg/6 h) and an even higher dose (10 mg/kg/6 h) failed to prevent the hyperamylasemia, acinar cell necrosis, and mortality that followed administration of a choline-deficient ethionine-supplemented diet. These observations are at variance with those previously reported to follow administration of the relatively weak cholecystokinin antagonist proglumide (Niederau C et al. J Clin Invest 1986;78:1056-63). The observations reported in this communication suggest that cholecystokinin does not play an important role in diet-induced pancreatitis and that CCK receptor antagonists are unlikely to be of benefit in the treatment of clinical acute pancreatitis.

Topics: Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Choline Deficiency; Devazepide; Diet; Ethionine; Female; Mice; Mice, Inbred Strains; Pancreatitis

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Topics: Acute Disease; Amylases; Animals; Cholecystokinin; Choline Deficiency; Disease Models, Animal; Ethionine; Female; Gabexate; Guanidines; Hemorrhage; Mice; Pancreas; Pancreatitis; Proglumide; Receptors, Cholecystokinin; Secretin; Time Factors; Trypsin

The earliest changes noted during the evolution of pancreatitis induced by feeding mice a choline-deficient ethionine-supplemented (CDE) diet are an increase in the number of zymogen granules in pancreatic acinar cells and an increase in digestive enzyme content of the pancreas. We have studied the processes of protein and digestive enzyme synthesis and discharge at varying times after institution of the CDE diet, a choline-deficient diet (CD), and a diet containing ethionine but not choline-deficient (E). Both the CDE and E diets increased digestive enzyme content within 12 h of their institution. Both the CDE and E diets reduced the rate of protein and amylase synthesis and caused a marked reduction in the rate of protein and amylase discharge from the pancreas. These changes were greatest and were noted earliest in the CDE diet group. A marked reduction in secretagogue-induced in vivo and in vitro amylase discharge followed ingestion of either the CDE or E diet. These studies indicate that the increased pancreatic content of digestive enzymes noted after ingestion of the CDE and E diets results from an ethionine-induced decrease in the rat of digestive enzyme discharge. This phenomenon is enhanced by simultaneous choline deficiency. Subsequent intrapancreatic activation of zymogens may couple these changes in enzyme content to the development of hemorrhagic pancreatitis.

Topics: Amylases; Animals; Cholecystokinin; Choline; Choline Deficiency; Chymotrypsinogen; Ethionine; Female; Mice; Pancreas; Trypsinogen