ONO-3403

Pancreatic exocrine secretion in conscious rats is mainly regulated by protease activities in the duodenum.A decrease in protease activities by oral administration of trypsin inhibitors (TI)s produces pancreatic hypertrophy via cholecystokinin (CCK) release.Since luminal CCK releasing factor (LCRF), was purified from rat intestine, we determined whether the levels of LCRF, CCK, and protein secretion were synchronized with each other.Changes in pancreatic secretion, plasma CCK levels, and LCRF contents produced by 2- and 4-h bile-pancreatic juice diversion (BPJD), were determined in rats with 7-day TI treatment and compared with controls.The levels of LCRF and CCK changed in parallel.Pancreatic protein secretion was higher in rats treated with TI than in controls throughout the exptl. period.The plasma CCK and luminal LCRF content 4-h after BPJD was significantly lower in rats treated with TI than in controls.The hypertrophied pancreas may require a smaller dose of CCK to increase protein secretion.

The pancreatic exocrine response to CCK-8 was examined and the mechanism of the pancreatic exocrine hypersecretion after oral administration of synthetic protease inhibitor ONO-3403 in rats was clarified.A single oral dose (20 μg/kg) of synthetic protease inhibitor ONO-3403 was given to rats by orogastric tube 6 h and 12 h before experimentsThe pancreatic juice was collected before test and after stimulation of stepwise increasing doses of cholecystokinin-8 (CCK-8).The output of protein, amylase, lipase and bicarbonate in pancreatic juice or pancreatic tissue were determined by Lowry method, Chromogenic method with blue-dyed starch polymer, Whitaker method and by the DST 800 multi-titration system, resp.Oral administration of ONO-3403 had no influence on pancreatic juice flow and output of protein in basal and CCK-8 stimulation at 6h after ONO-3403 pretreated, but it caused a significant increase in pancreatic juice flow (peak level 215 ± 9 μg per 30 min vs. 93 ± 6 μg per 30 min) and protein output (peak level 16475 ± 1801 μg per 30 min vs. 5920 ± 593 μg per 30 min) of the basal and CCK-8 stimulation at 12 h after ONO-3403 pretreated.The basal pancreatic juice flow and output of amylase (470 ± 32 su per 30 min at 6 h, 394 ± 47 su per 30 min at 12 h, vs. 251 ± 32 su per 30 min), bicarbonate (2.224 ± 0.333 μmol per 30 min at 6 h, 3.148 ± 0.374 μmol per 30 min at 12 h, vs. 1.428 ± 0.282 μmol per 30 min) were significant high after ONO-3403 pretreated that those of control group.There was no change in lipase output compared with control group.The pancreatic weight, pancreatic contents of protein and amylase in ONO-3403 pretreated rats were similar to those in control rats.ONO-3403 can increase pancreatic exocrine secretion and sensitivity to CCK-8 stimulation.The mechanism of ONO3403 induced pancreatic exocrine hypersecretion may be a feedback regulation of the pancreas by increasing CCK secretion.