Continuous infusion of cholecystokinin leads to down-regulation of the cholecystokinin-A receptor in the rat pancreas

Background: Infusion of sulphated cholecystokinin-8 (CCK-8S) in rats transi ently increased the proliferation of pancreatic acinar cells, whereas the C CK-A receptor antagonist devazepide decreased such proliferation. This effe ct ceased after 3 days. CCK-8S or devazepide injected twice daily induced a persistent effect on the cell proliferation involving the major cells of t he exocrine pancreas. The aim of this study was to examine the effect of co ntinuous infusion of CCK-8S and devazepide on CCK-A receptor gene expressio n. Methods: Male Sprague-Dawley rats received subcutaneous continuous infus ion of 5 mu g/kg/h CCK-8S, 200 mu g/kg/h devazepide, or 1% bovine serum alb umin (BSA) by means of osmotic minipumps; The rats were killed after 3 days ; 1 h before bring killed they received 5-broino-2-deoxyuridine (BrdU) intr aperitoneally. Plasma was collected for analysis of CCK. The pancreas was d issected, and indirect immunofluorescence for BrdU and CCK-A receptor was p erformed. In situ hybridization to CCK-A receptor mRNA was performed for ex amination and semiquantification of receptor gene expression. Results: Cont inuous infusion of CCK-8S led to a sixfold increase in plasma CCK and a 40% increase in pancreatic weight. Devazepide did not affect the CCK level but decreased the pancreatic weight by 24% compared with BSA-infused rats. The BrdU labeling indicated that CCK-8S had no effect on cell proliferation. I mmunofluorescence for the CCK-A receptor showed a decreased labeling intens ity after CCK-8S infusion. The mean optical density of in situ hybridizatio n labeling of the sections from CCK-8S-treated rats was decreased to 37% +/ - 3% of that in controls. Devazepide did not affect the CCK-A receptor gene expression. Conclusions: Continuous stimulation of the CCK-B receptor led to a downregulation of the receptor gene expression in pancreatic acinar ce lls and decreased labeling of the receptor at immunohistochemistry. The res ults suggest that down-regulation of the receptor is a protective mechanism against overstimulation.