We investigated the protective and/or
therapeutic effects of a new
cholecystokinin receptor antagonist,
KSG-504, on different types of experimental
pancreatitis in the rat and mouse. The
intravenous injection of
KSG-504 (10, 25, 50 and 100 mg/kg) before
caerulein administration to the rat inhibited the increases in plasma
amylase,
lipase and of pancreatic wet weight in a dose-dependent manner. The histological changes due to
caerulein-induced
acute pancreatitis were also decreased by
KSG-504 when
KSG-504 (25, 50 and 100 mg/kg) was administered after the induction of
acute pancreatitis; the increases in plasma
amylase,
lipase and pancreatic wet weight were reduced, but the histological changes of the pancreas were not decreased significantly. In the second experiment,
acute pancreatitis was induced in rats by injecting 0.3 ml of 6%
sodium taurocholate into the pancreatic interstitial tissue.
KSG-504 administered immediately and 1.5 hr after
sodium-taurocholate injection at 100 mg/kg reduced the increases of pancreatic
enzymes in the plasma, pancreatic wet weight and
ascites. Moreover,
KSG-504 (50 and 100 mg/kg, i.v., x 2) mitigated the histological changes of
taurocholate-induced
acute pancreatitis. Another type of
acute pancreatitis was induced in mice by dl-
ethionine (0.5 g/kg, p.o., x 4) and a
choline-deficient diet.
KSG-504 (10, 30 and 100 mg/kg) was subcutaneously administered five times every 12 hr during the experiment.
KSG-504 elongated the survival of mice in a dose-dependent manner. These findings suggest that
KSG-504 has potent protective and/or
therapeutic effects against
acute pancreatitis and that
cholecystokinin may be involved in the development of
pancreatitis.