Abstract

Mosapride citrate is a new gastroprokinetic agent that enhances the upper GI motility by stimulating 5-hydroxytryptamine₄(5-HT₄) receptors. The purpose of this study was to compare the effects of mosapride and the existing 5-HT₄ receptor agonists on GI motility in conscious dogs and on various 5-HT₄ receptor-mediated responses in vitro. In conscious dogs with force transducers implanted, mosapride (0.3–3 mg/kg i.v.) stimulated the antral motility without affecting the colonic motility. However, cisapride, zacopride and BIMU 8 (0.1–1 mg/kg i.v.) stimulated both antral and colonic motility. The enhanced GI motility induced by mosapride or cisapride was antagonized by pretreatment with GR113808 (1 mg/kg bolus i.v., thereafter 1 mg/kg/hr infusion), a selective 5-HT₄ receptor antagonist. In the receptor binding studies, mosapride inhibited [³H]-GR113808 binding to 5-HT₄ receptor sites of guinea pig striatum with an IC₅₀ value of 113 nM. In addition, mosapride caused relaxation of the carbachol-precontracted rat esophagus, enhanced the electrically evoked contractions of guinea pig ileum and evoked the contractions of guinea pig distal colon with EC₅₀ values of 208, 73, and 3029 nM, respectively; this indicates that mosapride has a low affinity for colon than for the rest of the GI tract. In contrast, cisapride, zacopride or BIMU 8 had similar potencies in all preparations examined. In conclusion, these studies indicate that mosapride selectively stimulates upper GI motility in vivo and in vitro. These results also suggest heterogeneity of 5-HT₄ receptors in the GI tract.