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Pancreaticobiliary diversion (PBD) and biliodigestive shunt (BDS) cause long-standing hypercholecystokininemia followed by pancreatic hyperplasia. These changes have been suggested to be due to the lack of intraluminal trypsin and bile, respectively, in the upper small intestine. The aim of these experiments was to study the effect of restoration of intraluminal trypsin and bile on plasma levels of cholecystokinin (CCK) and the changes found in exocrine and endocrine pancreas after PBD and BDS. Male Sprague-Dawley rats were used. PBD was done in 16 rats, eight of which had trypsin dissolved in 50 mM sodium bicarbonate (SB), and eight had SB only by gastric intubation twice daily. BDS was done in another 16 rats, eight of which had bile dissolved in SB, and eight had SB in a similar manner. Sham-operated rats had SB and served as controls. After 4 weeks, the rats were killed, and the concentrations of circulating CCK, gastrin, glucose, glucagon, and insulin were determined. The pancreas was removed, weighed, and analyzed for contents of water, protein, and DNA. In another study, PBD-operated rats got trypsin in varying dosages or trypsin and taurocholate in combination for 2 weeks before death. The concentrations of plasma CCK and glucagon were elevated after both PBD and BDS. PBD decreased the concentration of gastrin in plasma. PBD caused an increase of pancreatic weight and the contents of protein and DNA. Trypsin substitution to PBD-operated rats did not affect plasma CCK or glucagon levels, but the PBD-induced increases in weight and DNA content were counteracted by trypsin. Higher dosages of trypsin did not further influence the effects seen after PBD. Pancreatic weight and DNA content were increased after BDS. Bile administration completely abolished the increase in plasma CCK and glucagon, as well as the gain in pancreatic weight, and reduced the increase in pancreatic DNA. Substitution with bile to BDS-operated rats abolished the increase in the plasma levels of CCK and glucagon, as well as the trophic effects on the pancreas. Trypsin substitution to PBD-operated rats partly reversed the trophic effects on the pancreas but not the hormonal changes in plasma. Thus the trophic effects on the pancreas exerted by BDS seem to be dependent on the lack of bile in the upper small intestine, whereas the effects of PBD only partly are a consequence of the absence of intraluminal trypsin.
Pancreaticobiliary diversion (PBD) and biliodigestive shunt (BDS) cause long-standing hypercholecystokininemia followed by pancreatic hyperplasia. These changes have been suggested to be due to the lack of intraluminal trypsin and bile, respectively, in the upper small intestine. The aim of these experiments was to study the effect of restoration of intraluminal trypsin and bile on plasma levels of cholecystokinin (CCK) and the changes found in exocrine and endocrine pancreas after PBD and BDS. Male Sprague-Dawley rats were used. PBD was done in 16 rats, eight of which had trypsin dissolved in 50 mM sodium bicarbonate (SB), and eight had SB only by gastric intubation twice daily. BDS was done in another 16 rats, eight of which had bile dissolved in SB, and eight had SB in a similar manner. Sham-operated rats had SB and served as controls. After 4 weeks, the rats were killed, and the concentrations of circulating CCK, gastrin, glucose, glucagon, and insulin were determined. The pancreas was removed, weighed, and analyzed for contents of water, protein, and DNA. In another study, PBD-operated rats got trypsin in varying dosages or trypsin and taurocholate in combination for 2 weeks before death. The concentrations of plasma CCK and glucagon were elevated after both PBD and BDS. PBD decreased the concentration of gastrin in plasma. PBD caused an increase of pancreatic weight and the contents of protein and DNA. Trypsin substitution to PBD-operated rats did not affect plasma CCK or glucagon levels, but the PBD-induced increases in weight and DNA content were counteracted by trypsin. Higher dosages of trypsin did not further influence the effects seen after PBD. Pancreatic weight and DNA content were increased after BDS. Bile administration completely abolished the increase in plasma CCK and glucagon, as well as the gain in pancreatic weight, and reduced the increase in pancreatic DNA. Substitution with bile to BDS-operated rats abolished the increase in the plasma levels of CCK and glucagon, as well as the trophic effects on the pancreas. Trypsin substitution to PBD-operated rats partly reversed the trophic effects on the pancreas but not the hormonal changes in plasma. Thus the trophic effects on the pancreas exerted by BDS seem to be dependent on the lack of bile in the upper small intestine, whereas the effects of PBD only partly are a consequence of the absence of intraluminal trypsin.
Earlier studies have shown different effects on cell proliferation and weight characteristics by sulfated cholecystokinin-8 (CCK-8S) in the rat pancreas when the peptide has been administered continuously rather than intermittently. The aim of this study was as follows: (i) to compare the effect of continuous infusion and of intermittent injections of CCK-8S on cell proliferation, weight gain, and induction of apoptosis and (ii) to examine the effect of injections of CCK-8S on CCK-A receptor gene expression in the rat pancreas. Male Sprague-Dawley rats had subcutaneous continuous infusion of CCK-8S in a dose of 5 microg/kg/h or 1% bovine serum albumin (BSA) (vehicle) by implanted osmotic minipumps. The rats were killed after 4 days. Other rats were either injected subcutaneously only once or injected twice daily for 3 days with either 6 microg of CCK dissolved in 0.5 mL BSA or 0.5 mL BSA alone. The rats were killed 1, 3, 6, and 12 hours after the last injection. One hour before death they received 5-bromo-2-deoxyuridine (BrdU) intraperitoneally to localize and quantitate the cell proliferation. Plasma was collected for analysis of CCK. The pancreas was dissected and immunohistochemistry was performed for analysis of the expression of the apoptosis promoting protein bax and the apoptosis inhibiting protein bcl-2, and for BrdU and CCK-A receptor localization. In situ hybridization (ISH) was used for examination and semiquantification of CCK-A receptor mRNA expression. Continuous infusion of CCK-8S led to a sixfold increase in plasma CCK and a 40% increase in pancreatic weight without any effect on BrdU labeling. Immunohistochemistry revealed decreased tissue expression of bax but unaffected expression of bcl-2. Intermittent injections of CCK-8S led to hyper-CCK-emia with increased incorporation of BrdU, indicating increased cell proliferation but no increase in pancreatic weight. Immunohistochemistry showed increased expression of bax, whereas bcl-2 remained unchanged. Immunofluorescence and ISH for the CCK-A receptor and its gene expression, respectively, showed a lowest intensity at 3 hours after CCK-8S injections. The results indicate that decreased apoptosis could explain the increased pancreatic weight during continuous infusion of CCK-8S. An increased apoptosis could explain the lack of pancreatic weight gain upon intermittent injections of CCK-8S despite the stimulation of cell proliferation. Injections of CCK-8S only transiently decreased the tissue levels of its receptor.
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