The proposed research is aimed at establishing the biological significance of several GI regulatory peptides designated as candidate enterogastrones. Previous studies have suggested that these peptides, particularly those belonging to the secretin family, may be involved in the regulation of acid secretion. The proposed experiments, which constitute a continuation and extension of those presently funded by Clinical Investigator Award K08 AM01640, will also investigate the complex interrelationships among these regulatory peptides and gastrin and somatostatin. These studies will utilize in vivo and vitro methods, including antral mucosal tissue incubation, the isolated vascularly perfused rat stomach, and the isolated luminally perfused mouse stomach, as well as several immunochemical techniques. Regulatory peptides to be studied include members of the secretin family -secretin, gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), and peptide HI (PHI) - and somatostatin and peptide YY (PYY). The proposed experiments will examine the potential physiologic roles of secretin, GIP, VIP, PHI, and PYY in affecting gastrin and somatostatin synthesis and release and whether these effects are a result of direct interaction with gastrin cells or are mediated locally through somatostatin. These studies will be performed using short term antral mucosal incubation, which offers the advantage of permitting direct assessment of peptide interaction, and the isolated perfused rat stomach, which provides an ideal system for investigating peptides that exert their effects through systemic pathways. The isolated perfused rat stomach will also be used to determine whether neural pathways are involved in exerting he effects of secretin-like peptides on gastrin and somatostatin release. The effects of secretin-like peptides on gastrin and somatostatin synthesis will be investigated using antral mucosal tissue incubation and measuring incorporation of 35S-methionine into gastrin and 35S-cysteine into somatostatin. Gastrin synthesis will also be examined using region-specific antisera directed against the C-terminal extended precursor peptide. The isolated mouse stomach will be used to determine whether the effects of secretin-like peptides on parietal cells are direct or mediated through local somatostatin. Finally, the acid secretory response to secretin, GIP, and PYY will be examined in vivo in rats prepared with jugular catheters and pyloric drainage tubes.
