Abstract

Previous studies have shown that the intestinal peristaltic reflex initiated by mucosal stimulation is mediated by release of 5-hydroxytryptamine (HT) from enterochromaffin cells; 5-HT acts via 5-HT₄ receptors in rat and human, and via both 5-HT₄ and 5-HT₃ receptors in guinea pig to activate intramural sensory neurons that release calcitonin gene-related peptide. In this study, selective agonists and antagonists were used to examine the involvement of 5-HT₄ and 5-HT₃ receptors in colonic propulsion. The velocity of propulsion was measured with artificial fecal pellets introduced into the orad end of an isolated guinea pig colonic segment. Control velocity ranged from 0.5 to 3.3 mm/s; mean ± S.E.M., 1.3 ± 0.1 mm/s. The 5-HT₄ antagonist, GR 113808A, and the 5-HT₃ antagonist, LY 278584, decreased the velocity of pellet propulsion in a concentration-dependent fashion (39 ± 2% and 47 ± 1% decrease at 10 μM, respectively). A combination of both antagonists (10 μM each) was additive, decreasing the velocity by 82 ± 3% to 84 ± 4%. The selective 5-HT₄agonists, HTF 919 and R093877, as well as 5-HT in the presence of the 5-HT_2a antagonist, ketanserin, increased the velocity of propulsion in a concentration-dependent fashion with EC₅₀s of 6.9 ± 0.1 nM, 37.4 ± 1.0 nM, and 3.9 ± 0.1 nM, respectively. Compared with HTF 919, R093877 was less potent and appeared to be a partial agonist. All three agonists were effective at submicromolar concentrations; at concentrations above 1 μM, there was no increase in the velocity of propulsion. We conclude that the presence of fecal pellets triggers the release of 5-HT, which acts via both 5-HT₃ and 5-HT₄ receptors to regulate propulsive activity in guinea pig colon.