LONG-TERM BLOCKADE OF CHOLECYSTOKININ (CCK) - EFFECTS OF L-364,718 (ACCK RECEPTOR ANTAGONIST) ON PANCREATIC-ENZYME STORAGE AND SECRETION

To determine the effect of long-term blockade of cholecystokinin (CCK) on both pancreatic storage and secretion processes, L 364,718 (a CCK receptor antagonist) was administered to rats at 0.1 mg/kg/day for 3, 7, and 15 days. Zymogen granules were analyzed by flow cytometry to de termine their light scattering properties-forward scatter and side sca tter-as well as their amylase content measured by a specific antiserum . The mean number of zymogen granules per cell was counted on pancreat ic sections using electron microscopy. DNA content, pancreatic weight, and enzyme secretion were also studied under both basal conditions an d CCK infusion at a dose of 1.25 mu g/kg/h, which is able to displace the CCK receptor antagonist. Two subpopulations of zymogen granules (Z (1) and Z(2)) were identified on the basis of their light scattering p arameters, in both control and L 364,718-treated rats. L 364,718 admin istered for 3, 7, and 15 days induced a significant reduction in the a mylase content of individual zymogen granules, for both Z(1) and Z(2) zymogen granule subsets. In contrast, the number of zymogen granules p er cell increased from day +3 of treatment onward, the highest values being detected at day +7. Hyperplasia was observed only at day +15. Ba sal enzyme secretion decreased significantly in rats treated with L 36 4,718 for 3 and 7 days but recovered to control values after 15 days o f treatment. No significant differences in CCK-stimulated amylase secr etion were observed between control and L 364,718-treated rats. At day +15 of L 364,718 treatment a significant increase in enzyme secretion was observed with respect to shorter treatment periods; this was asso ciated with a significant increase in both the number of cells and the number of zymogen granules per cell. Our results indicate that chroni c administration of L 364,718 induces a biphasic effect on pancreatic function. interestingly, although enzyme secretion reached recovery af ter long-term treatment (15 days), the storage process is altered sinc e the mean enzyme content in each individual zymogen granule remains s ignificantly reduced.