sincalide and Choline-Deficiency

In order to approach impaired stimulus-secretion coupling in acute pancreatitis induced by a choline-deficient, ethionine-supplemented (CDE) diet in mice, the agonist-evoked intracellular Ca2+ dynamics of dispersed pancreatic acini were evaluated by microspectrofluorometry. Mice were fed a CDE diet for 24 or 48 h, and the pancreas was dispersed to the acini. The in vitro amylase secretion analysis of the CDE groups demonstrated a poor dose-response curve which was significantly lower (p < 0.01) when 100 pM cholecystokinin (CCK) was administered. Both in CDE and control groups, the application of a physiological dose of CCK-8 (10 pM) evoked intracellular Ca2+ oscillations. Periodicity and amplitude of the oscillations in the CDE groups were not significantly different. The administration of a higher dose of CCK-8 (100 pM) evoked a large, sharp, and transient rise in intracellular Ca2+, followed by a small, continuous increase above basal levels for the duration of stimulation both in CDE and control groups. The peak Ca2+ level was lower in the CDE groups, but this was not statistically significant. In conclusion, during the early phase (from 24 to 48 h) of CDE pancreatitis, the pattern of agonist-evoked intracellular Ca2+ release is less affected. Other mechanisms subsequent to the onset of intracellular Ca2+ release are likely to be involved in the inhibition of enzyme secretion.

Topics: Acute Disease; Amylases; Animals; Calcium; Choline Deficiency; Ethionine; Female; In Vitro Techniques; Mice; Pancreas; Pancreatitis; Sincalide

Little is known about exocrine pancreatic secretory function in patients with acute pancreatitis, in particular during the early phase of the disease. Therefore, this study evaluates basal and stimulated pancreatic secretion in vivo and in vitro in four different models of acute pancreatitis which reflect its clinical spectrum of severity: (a) edematous pancreatitis induced in the rat by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (b) edematous pancreatitis with cellular necrosis induced in the mouse by seven IP injections of 50 micrograms/kg cerulein at hourly intervals; (c) hemorrhagic pancreatitis induced in the mouse by feeding an ethionine-supplemented, choline-deficient diet for 66 hours; and (d) hemorrhagic pancreatitis induced in the rat by retrograde infusion of 0.6 mL 5% sodium taurocholate into the pancreatic duct. Secretory studies were performed in vivo and in vitro at various times after onset of pancreatitis. The results show that the exocrine pancreas gradually became resistant to cholecystokinin stimulation after the onset of acute pancreatitis in all four animal models. Cholecystokinin-stimulated secretion was almost abolished in vivo and in vitro at the time of maximal histological damage. In vivo basal secretion was also reduced. In vitro there was an increase in basal release of amylase from isolated acini that was not caused by an increase in luminal secretion but by enzyme release from damaged cells. The time course of improvement of secretory function after acute experimental pancreatitis depended on the severity of the pancreatitis. Recovery of secretory capacity took longer after severe necrotizing pancreatitis than after edematous pancreatitis. However, the ultimate resolution of secretory function was remarkable, in particular after severe hemorrhagic pancreatitis. In all four models, secretory capacity became indistinguishable from normal before the morphological alterations had completely resolved. The present experimental data suggest that pancreatic secretion, and particularly pancreatic secretory response to cholecystokinin, may also be reduced in patients early after the onset of acute pancreatitis.

Topics: Acute Disease; Animals; Ceruletide; Choline Deficiency; Diet; Female; Male; Mice; Pancreas; Pancreatic Juice; Pancreatitis; Rats; Rats, Inbred Strains; Sincalide; Taurocholic Acid

The mechanism that explains the association between corticoids and acute pancreatitis is unknown. Our hypothesis was that chronic glucocorticoid treatment could adversely affect the course of hemorrhagic pancreatitis by acting through cholecystokinin (CCK) receptors. Acute necrotizing pancreatitis was induced by feeding young female mice a choline-deficient, ethionine-supplemented (CDE) diet for 60 hours. Treatment with hydrocortisone (10 mg/kg/day) was begun 1 week before pancreatitis. At the onset of the CDE diet, a group of hydrocortisone-treated mice were also given the CCK receptor antagonist CR-1409 (5 mg/kg three times a day). Control mice received injections of saline solution. A follow-up of 336 hours was conducted for survival analysis. Hydrocortisone given alone did not produce pancreatitis. Hydrocortisone, however, did increase the pancreatic necrosis caused by the CDE diet (from 40% to 70%) and significantly reduce survival (from 40% to 9%). CR-1409 completely abolished the adverse effects of hydrocortisone on pancreatitis. We measured amylase release by dispersed pancreatic acini from mice chronically treated with hydrocortisone in response to CCK-8. Treatment with hydrocortisone increased both the sensitivity and the responsiveness of the pancreas to CCK-8. We conclude that glucocorticoids alone may not induce acute pancreatitis, but they can increase the risk of a more severe form of pancreatitis developing. The glucocorticoid effect appears to be attributable to a CCK receptor-mediated sensitization of the pancreas to endogenous CCK. Thus, CCK-receptor blockade may improve survival in necrotizing pancreatitis associated with chronic glucocorticoid treatments.

Topics: Amylases; Animals; Choline Deficiency; Diet; Dose-Response Relationship, Drug; Ethionine; Female; Glucocorticoids; Hydrocortisone; Mice; Mice, Inbred Strains; Necrosis; Pancreas; Pancreatitis; Proglumide; Receptors, Cholecystokinin; Sincalide