STIMULATORY MECHANISM OF EM523-INDUCED CONTRACTIONS IN POSTPRANDIAL STOMACH OF CONSCIOUS DOGS

Background & Aims: EM523, a motilin agonist, is intended to be used as a gastroprokinetic during the postprandial period, but the mechanism(s) by which EM523 stimulates postprandial contractions in the stomach has not been studied before. The aim of this study was to examine the mechanism of contraction-stimulating activity by EM523 in fed dogs. Methods: Contractile activity in the gastric antrum of 5 dogs was monitored using a long-term implanted force transducer and measured by integrating the area under the curve. Test materials weve continuously infused or injected intravenously. Results: EM523 (1-30 mu g/kg) induced a dose-dependent increase in fed-type contractions. EM523-induced contractile activity was partially inhibited by atropine, hexamethonium, dopamine, 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, and substance P antagonist. Atropine-resistant and EM523-induced contractions were further inhibited by 5-HT, receptor antagonist and substance P antagonist, and the combined use of the two antagonists completely eliminated the atropine-resistant and EM523-induced contractions. Conclusions: EM523-induced contractions in the fed stomach are quite different from phase III contractions in the fasted state and ave mediated partially through the cholinergic pathway. The noncholinergic pathway involves 5-HT3 and neurokinin 1 receptors.