Stimulation of pancreatic secretory process in the rat by low-molecular weight proteinase inhibitor. I. Dose-response study on enzyme content and secretion, cholecystokinin release and pancreatic fine structure.
Application of a single dose of a new type of proteinase inhibitor camostate (FOY-305) via orogastric tube was used in rats to study the dose-response relationship of resulting pancreatic stimulation. Doses up to 10 mg/kg failed to elicit any response, while significant decrease in enzyme content and increase in serum CCK-levels were observed with doses ranging from 25 to 400 mg/kg. A single dose of 100 mg/kg was selected for a time-sequence analysis, which revealed a 60 to 70% depletion of enzyme stores persisting over 6 h and reverting to control levels by 12 h. Peak increases in serum CCK-levels (15-fold above the elevation observed after regular food intake) were found after 30 min and persisted as an 8- to 10-fold elevation for at least 3 h, then declined to control levels by 9 h. This prolonged endogenous hormone release and resulting pancreatic stimulation were also verified in a separate group of animals in which volume, protein, and enzyme output were measured after cannulation of the pancreatic duct. While volume secretion was not altered by feeding a single dose of 100 mg/kg FOY-305, protein and enzyme output increased 2- to 3-fold over a period of 7 h. Fine-structural analysis of the pancreas demonstrated efficient depletion of zymogen granules from acinar cells with all doses between 50 and 400 mg/kg, accompanied by the appearance of membrane material in the acinar lumina at 3 and 6 h. The same transient increase in the number of lysosomal bodies predominantly containing mitochondria with all doses above 50 mg/kg was interpreted as increased organelle turnover due to persisting hormonal stimulation.
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002766:Cholecystokinin / Q000097:blood / Q000378:metabolism*; D002918:Chymotrypsin / Q000378:metabolism; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006056:Golgi Apparatus / Q000648:ultrastructure; D006146:Guanidines / Q000494:pharmacology*; D007700:Kinetics; D008049:Lipase / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014357:Trypsin / Q000378:metabolism
D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; C034532:camostat; D016670:Gabexate; D002766:Cholecystokinin; D008049:Lipase; D000681:Amylases; D002918:Chymotrypsin; D014357:Trypsin