Improved experimental models have recently been developed for the study of acute pancreatitis, a disease for which at present no specific therapy exists. Studies in these models suggest that cholecystokinin (CCK), a hormonal stimulant of pancreatic secretion, may be a contributory factor in the development of acute pancreatitis and that substances which block the effects of CCK on the pancreas may be therapeutically beneficial. The proposed studies are designed to evaluate further how CCK effects the metabolism of the pancreas in the normal state and how this might lead to worsening the harmful processes involved in pancreatitis. In the first set of experiments, a newly described, highly potent inhibitor of CCK will be evaluated in severe acute pancreatitis induced in mice by a special diet to determine whether this agent is therapeutically beneficial. If it is, its effects will be compared to a previously studied, structurally different inhibitor of CCK to assess whether particular structural properties are important in producing a therapeutic effect. In the second set of studies, the ability of isolated pancreatic secretory cells to bind CCK will be evaluated at different stages in the development of acute pancreatitis to determine if changes in binding of CCK are related to its harmful effects. The third category of experiments uses magnetic resonance spectroscopy of the pancreas by means of a coil implanted around the pancreas in living animals to determine the effects of CCK on important high-energy phosphate compounds both in the normal state and in pancreatitis. In the fourth set of experiments, CCK's effect on oxygen use by isolated pancreatic acini (groups of secretory cells) will be studied in tissue from normal animals and animals with pancreatitis. The final experiments examine whether CCK alters the stability of zymogen granules (storage compartments for digestive enzymes in the pancreas) under normal conditions and in pancreatitis. The proposed research should answer important questions about the function of the pancreas both in the healthy state and in disease and may lead to a new and effective approach to the treatment of acute pancreatitis.
