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-HT2a 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.
Footnotes
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Send reprint requests to: J.R. Grider, Doctor of Philosophy, P.O. Box 980551, Medical College of Virginia, Richmond, VA 23298-0551.
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↵1 This work was supported by Grant DK-34153 from the National Institute of Diabetes and Digestive and Kidney Diseases.
- Abbreviations:
- CGRP
- calcitonin gene-related peptide
- 5-HT
- 5-hydroxytryptamine
- LY 278584
- 1-methyl-N-(8-methyl-8-azabicyclo[3.2.l]-oct-3-yl)-lH-indazole-3-carboxamide maleate
- SDZ 205557
- 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester
- HTF 919
- 5-methoxy-indole-3-carboxaldehyde amino(pentylamino) methylene hydrazone hydrogen maleate
- GR 113808A
- [I-[2-(methylsulfonyl amino)ethyl]-4-piperidinyl]methyl 1-methyl-lH-indole-3-carboxylate, maleate salt
- R093877
- 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxy propyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride
- Received March 12, 1998.
- Accepted July 22, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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