Effect of nonpeptide motilin agonist EM523 on release of gut and pancreatic hormones in conscious dogs.

Abstract

EM523, a nonpeptide motilin agonist, is being developed 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. Motility of the gastrointestinal tract was monitored using force transducers. Blood concentrations of gut and pancreatic hormones were measured using a specific radioimmunoassay. EM523 (3 micrograms/kg) or normal saline (5 mL) was given during the phase I period of the interdigestive state. A single injection of EM523 always induced phase III-like contractions in the intact gastric antrum and was accompanied by significant (P < 0.01) release of motilin, pancreatic polypeptide, and insulin; glucagon, gastrin, cholecystokinin, and secretin were not released by EM523. The significant release of these hormones was suppressed by pretreatment with atropine and completely eliminated by a 5-hydroxytryptamine 3 receptor antagonist and truncal vagotomy. The findings suggest that EM523 stimulates the release of pancreatic polypeptide, insulin, and motilin by activating the cholinergic parasympathetic nerve system, finally stimulating the endocrine pancreas through vagally cholinergic muscarinic receptors in the pancreatic islets. The participation of 5-hydroxytryptamine 3 receptors in this system is strongly suggested by the results.