Blockage of the rat pancreatico-biliary duct (PBDO) for 4 hours and secretin infusion (0.2 CU [Clinical Unit]/kg/hr) caused significant rises in portal serum amylase, cathepsin B levels, pancreatic water content, and pancreatic amylase content as well as lysosomal and mitochondrial fragility. Impaired pancreatic adenylate energy charge levels were also noted. These changes tended to continue for 12 hours after the release of PBDO and disappeared after 24 hours. All the changes induced by PBDO with secretin infusion were no longer observed at 48 hours. The administration of a new potent protease inhibitor, E-3123 at a dose of 5 mg/kg/hr during PBDO markedly attenuated all the parameters examined, exerting a significant protective effect on acinar cells in this model. These results indicate the important roles of subcellular organelle fragility and impaired pancreatic energy metabolism in the pathogenesis of pancreatic injuries induced by common channel obstruction with intraductal hypertension, and also indicate the possible usefulness of E-3123 in the treatment of acute pancreatitis such as gallstone pancreatitis.
