Mechanisms for the stimulation of pancreatic secretion have been investigated intensively but there is a paucity of information about the mechanisms of inhibition. This proposal examines the mechanism by which peptides from the intestine and pancreas suppressed exocrine secretion. Preliminary studies have shown that firstly, somatostatin inhibits pancreatic secretion in the intact animal and in the isolated, vascularly perfused rat pancreas but not in dispersed isolated acini; and secondly, tetrodotoxin, which blocks axonal transmission, abolishes this inhibitory action of somaostatin. These observations lead to the hypothesis that somatostatin does not act directly on the acinar cell, but rather influences neurones within the pancreas either to stimulate the release of a secondary inhibitor or to suppress the release of a stimulatory or permissive factor.
The specific aims of the proposal are, therefore, (1) to examine the direct and indirect effects of inhibitory peptides; (2) to determine the contribution of intrinsic neurones to the mechanism of inhibition; (3) to identify the chemical mediator of neuronal inhibition; and (4) to develop a method to isolate and explant intrinsic pancreatic neurons so as to study directly the release of neurotransmitters involved in the inhibitory process. The strategy is to study somatostatin as a representative inhibitor if all of the peptides act indirectly. If, however a direct acting peptide is found the possibility that it is common final mediator will be examined. The role of intrinsic pancreatic neurons will be studied in the isolated, perfused rat pancreas by using tetrodotoxin and by testing whether somatostatin inhibits the release of stimulatory neurotransmitters (acetylcholine, vasoactive intestinal polypeptide, gastrin releasing peptide and cholecystokinin) in the isolated perfused rat pancreas and in pancreatic slices. If pancreatic neurons can be successfully grown in culture, both the tissue expression and release of neurotransmitters will be studied directly using immunocytochemistry and radioimmunoassay, respectively. The knowledge gained about mechanism of inhibition will be applied in the prevention and treatment of pancreatitis and in the field of pancreatic transplantation.
