EFFECT OF NONPEPTIDE MOTILIN AGONIST EM523 ON RELEASE OF GUT AND PANCREATIC HORMONES IN CONSCIOUS DOGS

Background & Aims: EM523, a nonpeptide motilin agonist, is being devel oped for clinical use to improve delayed gastric emptying, The aim of this study was to examine the effect of EM523 on endogenous release of gut and pancreatic hormones in conscious dogs, Methods: Motility of t he gastrointestinal tract was monitored using force transducers. Blood concentrations of gut and pancreatic hormones were measured using a s pecific radioimmunoassay. EM523 (3 mu g/kg) or normal saline (5 mL) wa s given during the phase period of the interdigestive state. Results: A single injection of EM523 always induced phase Ill-like contractions in the intact gastric antrum and was accompanied by significant (P < 0.01) release of motilin, pancreatic polypeptide, and insulin; glucago n, gastrin, cholecystokinin, and secretin were not released by EM523. The significant release of these hormones was suppressed by pretreatme nt with atropine and completely eliminated by a 5-hydroxytryptamine 3 receptor antagonist and truncal vagotomy, Conclusions: The findings su ggest that EM523 stimulates the release of pancreatic polypeptide, ins ulin, and motilin by activating the cholinergic parasympathetic nerve system, finally stimulating the endocrine pancreas through vagally cho linergic muscarinic receptors in the pancreatic islets. The participat ion of 5-hydroxytryptamine 3 receptors in this system is strongly sugg ested by the results.