Participation of a cholinergic mechanism in 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptor-mediated stimulation of gastric emptying in rats.

The participation of a cholinergic mechanism in 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptor-mediated stimulation of gastric emptying in rats was investigated. The selective 5-HT3 receptor antagonists ramosetron (YM060, 0.1-10 micrograms/kg i.v.) and ondansetron (1-100 micrograms/kg i.v.) dose-dependently enhanced the gastric emptying of glass beads in rats. The 5-HT4 receptor agonist 5-methoxytryptamine (5-MOT, 1 mg/kg s.c.) and substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride (1-10 mg/kg s.c.) and zacopride (1-1000 micrograms/kg s.c.) produced significant gastroprokinetic responses in rats. The substituted benzamide-induced gastroprokinetic responses were inhibited by a high dose of tropisetron (10 mg/kg s.c.), a 5-HT3 and 5-HT4 receptor antagonist, and partially inhibited by GR113808 ([1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidyl]methyl 1-methyl-1H-indole-3-carboxylate, 1 mg/kg s.c.), a selective 5-HT4 receptor antagonist. On the other hand, the 5-MOT-induced gastroprokinetic response was almost completely inhibited by GR113808. In contrast, tetrodotoxin (TTX, 0.1-10 micrograms/kg s.c.) and atropine (1-1000 micrograms/kg s.c.) dose-dependently inhibited gastric emptying. The enhancement of gastric emptying induced by selective 5-HT3 receptor antagonists, substituted benzamides and 5-MOT was inhibited by TTX (10 micrograms/kg s.c.) and by atropine (1 mg/kg s.c.). These results suggest that substituted benzamides stimulated gastric emptying partly due to their 5-HT4 receptor agonistic properties, and that both 5-HT3 receptor antagonism and 5-HT4 receptor agonism stimulated the gastric emptying in rats. It is also suggested that a cholinergic mechanism participates in the 5-HT3 and 5-HT4 receptor-mediated stimulation of gastric emptying in rats.