Effects of the cholecystokinin A receptor antagonist loxiglumide on the proliferation and cell cycle time of pancreatic acinar cells in rats.
OBJECTIVE
Prior studies have indicated that endogenous or exogenous cholecystokinin (CCK) induces transient acinar cell proliferation at about 24 hours after its stimulation. The aims of the present study were to determine the time point when the administration of the CCK-A-receptor antagonist loxiglumide had its maximal suppressive effect on the proliferation of pancreatic acinar cells and to investigate the effects of loxiglumide on the cell cycle time of pancreatic acinar cells during transient acinar cell proliferation induced by endogenous or exogenous CCK.


METHODS
Eight-week-old Wistar rats were divided into the following groups: preadministration of loxiglumide (40 mg/kg) intravenously at 120, 60, and 0 minutes before endogenous CCK stimulation induced by a single oral administration of camostat (50 mg/kg) or exogenous CCK stimulation by a subcutaneous injection of CCK-8 (6 g/kg body weight). For the controls, intravenous saline was used instead of loxiglumide (n = 7 in each group). The proliferative activity of pancreatic acinar cells at 24 hours after CCK stimulation and the cell cycle time of these proliferating pancreatic acinar cells were studied using an immunohistochemical technique.


RESULTS
The most significant suppression of the proliferation of the acinar cells was observed in those groups which received loxiglumide 60 minutes before CCK stimulation (P < 0.016), but preadministration of loxiglumide had no effect on the cell cycle time of the proliferating acinar cells (not significant).


CONCLUSIONS
CCK antagonist loxiglumide is expected as an excellent clinical applicable agent for acute pancreatitis. Previous researches suggest that CCK is an aggravating factor during the acute phase of acute pancreatitis, but CCK may be a healing factor during the recovery period. From the results of the present study, it can be said that the excess chronic administration of CCK antagonists during the acute phase of acute pancreatitis may prevent any regrowth of pancreatic cells during the healing period of acute pancreatitis.
Graduate School of Medical Science, Molecular Gastroenterology, and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. daik@koto.kpu-m.ac.jp
Daisuke
D
Kanemitsu
Junichi
J
Sakagami
Tomoko
T
Motoyoshi
Tomoki
T
Nakajima
Keisho
K
Kataoka
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*
D006727:Hormone Antagonists; D043887:Receptor, Cholecystokinin B; C053737:loxiglumide; D011377:Proglumide