ENZYME CHANGES IN ZYMOGEN GRANULES AND IN PANCREATIC-SECRETION THROUGHOUT LONG-TERM CCK TREATMENT

Pancreatic enzyme storage and secretion were studied in rats treated t wice daily with SC injections (5 mu g/kg) of CCK-8 for 3, 7, and 15 da ys. Isolated zymogen granules were analyzed by flow cytometry to deter mine their FSC (forward scatter), SSC (side scatter), and amylase and trypsinogen contents. DNA content, pancreatic weight, and both basal a nd stimulated pancreatic secretion under IV CCK infusion (1.25 mu g/kg /h) were also studied. Two subsets of zymogen granules were identified by flow cytometry in both control and CCK-treated rats on the basis o f FSC and SSC parameters: Z(1) (smaller and less complex) and Z(2). Bo th subsets displayed a high degree of heterogeneity with respect to th eir enzyme content per zymogen granule. During the first 7 days of CCK treatment, hyperplasia and hypertrophy developed in the rats together with changes in the zymogen granules, reflected by a significantly de creased FSC, an increased SSC, and an increase in the mean trypsinogen /amylase ratio per granule. A rise in pancreatic enzyme secretion, esp ecially of trypsin, was observed. After 15 days of CCK administration, a simultaneous decrease in amylase content and increase in trypsinoge n content per zymogen granule was observed. A desensitization of the p ancreas to CCK happened after 15 days of CCK administration, reflected by a reduction of all the pancreatic functions that had been increase d at shorter CCK administration periods. Nevertheless, trypsinogen app eared resistant to desensitization because its secretion significantly increased in response to an IV infusion of CCK. CCK treatment display ed a differential packaging of the enzymes in individual zymogen granu les; the trypsinogen/amylase ratio was significantly higher in Z(2) zy mogen granules than in Z(1) subset throughout the treatment. (C) 1997 Elsevier Science Inc.