Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog.

The effects of IV injection of 5-hydroxytryptamine 3 receptor antagonists (BRL 43694 and GR38032F) on gastrointestinal contractile activity were studied in dogs with vagally denervated fundic pouch in the conscious state by means of chronically implanted force transducers in the gastrointestinal tract and the pouch. In the interdigestive state, 5-hydroxytryptamine 3 receptor antagonists (0.01-0.1 mg/kg), if given during phase III contractions, instantly and dose-dependently inhibited the spontaneous and motilin-induced phase III contractions in the intact stomach and altered the duodenal phase III contractions to a pattern of continuous contractions, the contractile force which was 65% of the spontaneous phase III contractions in the duodenum and caused immediate caudad migration of phase III contractions along the small intestine. However, the spontaneous and motilin-induced phase III-like contractions in the denervated pouch were not affected at all by 5-hydroxytryptamine 3 receptor antagonists. When 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) were given during the phase I period, they did not directly stimulate gastrointestinal contractions. The cyclic fluctuation of the plasma motilin concentration with phase III activity in the stomach was also not influenced by 5-hydroxytryptamine 3 receptor antagonists, but the next phase III contractions in the stomach were inhibited. During the digestive state, however, 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) did not influence contractile activity in the gastrointestinal tract and in the vagally denervated fundic pouch. On the basis of recent pharmacological studies showing that the distribution of 5-hydroxytryptamine 3 receptors is recognized in the area postrema, peripheral neurons of vagal afferents, and the enteric nervous system, the results of the current study provide a basis for a hypothesis that 5-hydroxytryptamine 3 receptor antagonists are most likely to block motilin-induced signals at 5-hydroxytryptamine 3 receptors on the vagal afferents. In conclusion, the present findings suggest the possible involvement of 5-hydroxytryptamine 3 receptors on vagal afferents especially in terms of endogenous release of acetylcholine in the control of interdigestive phase III activity in the stomach by motilin.