Stimulation of pancreatic secretory process in the rat by low-molecular weight proteinase inhibitor

Abstract

Previous studies with rats have shown that a single oral dose of the proteinase inhibitor Camostate (FOY-305) induces release of cholecystokinin (CCK) into the circulation, which lasts for 3 to 6 h. This transient endogenous release of hormone results in a depletion of pancreatic enzyme stores within 1 h and an increase in total rate of protein synthesis, which peaks at 6 to 9 h. At the level of individual enzyme biosynthesis a transient decrease in amylase and an increase in trypsinogen and chymotrypsinogen is observed. In the present study the time course of DNA synthesis and the labeling index of 5 populations of pancreatic cells have been analysed following a single oral dose of 50 or 100 mg/kg proteinase inhibitor, using in vivo labeling with 12 microCi/g body weight 3H-thymidine 1 h prior to sacrifice of the animals. DNA synthesis did not change during the initial 12 h following inhibitor feeding and then showed a phasic increase with a peak (20-fold) at 24 h and intermediate increases (4- to 5-fold) at 18 and 36 h, respectively. From the 5 pancreatic cell populations studied by autoradiography the labeling indices of interlobular duct cells and islet cells did not change over the entire observation period. Acinar cells, intralobular duct cells and interstitial cells showed a marked increase in labeling index with peak values at 24 h, which were 20-fold in acinar cells and 5.5- and 8.5-fold in intralobular duct cells and interstitial cells, respectively. The data demonstrate a significant growth response of pancreatic acinar tissue after a single episode of endogenous CCK-release, which is similar in extent, time course and cellular source as previously demonstrated during persistent stimulation of the pancreas by prolonged infusion of the CCK-analogue caerulein.

Diurnal pattern of rat pancreatic acinar cell replication

“…We suppose that this difference is due to the anesthesia we applied to the rats before treating them with the CCK receptor antagonist and with cerulein In attempt to find the mechanism which connects food intake with pancreatic acinar cell replication, we analysed the function of cholecystokinin (CCK) in this process. CCK has been shown to be a potent stimulator of pancreatic growth in the rat, either by infusion experiments of the CCK analog cerulein (Lütcke et al 1987), or by elevation of endogenous CCK by feeding serine proteinase inhibitors (Oates and Morgan 1982;Elsässer et al 1990). Here we used the CCK receptor antagonist L-364,718 (Wank 1995) to investigate the influence of CCK on the steady state acinar cell replication.…”

“…This strongly implies that the proliferative activity of rat pancreatic acinar cells depends on food intake. Previous studies inducing acinar cell proliferation in normal fed rats (Lütcke et al 1987;Elsässer et al 1990)have shown that there is a lag period of about 24 h between stimulating quiescent acinar cells to enter the cell cycle and the onset of S-phase. These results and our observation that the restoration of proliferative activity in those cells takes 24±48 h indicate that acinar cells in the S-phase around midnight had already been stimulated to enter the cell cycle during the eating period 24 h before.…”