Effect of KSG-504, a new CCK-A-receptor antagonist, on experimental acute pancreatitis in rats and mice

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.