Abstract
In five fasting, conscious dogs, we compared the prokinetic action of two selective 5-hydroxytryptamine-4 (5-HT4) receptor agonists with low affinity for 5-HT3 receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-methoxybenzoate) in the duodenum and jejunum, using cisapride as a reference compound. Heart rate and rate-corrected QT (QTc) also were monitored to assess whether or not the cardiac effects of cisapride are shared by other 5-HT4 receptor agonists. Both ML10302 and SR59768 dose-dependently stimulated spike activity in the duodenum with similar potencies (dose range, 3–300 nmol/kg i.v.; ED50 values: 24 and 23 nmol/kg i.v., respectively), mimicking the effect of cisapride (30–3000 nmol/kg i.v.). The maximal effect was achieved with the dose of 100 nmol/kg i.v. for both compounds. Similar findings were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate, selective 5-HT4 receptor antagonist), at doses having no effect per se, antagonized intestinal prokinesia by maximal doses of ML10302 and SR59768. Neither ML10302 nor SR59768 had any effect on heart rate or QTc at any of the doses tested, whereas cisapride, at the highest dose (3000 nmol/kg), induced tachycardia and lengthened the QTC (p < .01). In conclusion, ML10302 and SR59768 share with cisapride a similar prokinetic action in the canine duodenum and jejunum in vivo. This effect is mediated by pathways involving activation of 5-HT4 and muscarinic receptors. Unlike cisapride, which induces tachycardia and prolongs the QTc by a mechanism probably unrelated to 5-HT4 receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.
Footnotes
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Send reprint requests to: Dr. Fabrizio De Ponti, Department of Internal Medicine and Therapeutics, Section of Pharmacology and Toxicology, Piazza Botta 10, I-27100 Pavia PV, Italy. E-mail:deponti{at}ipv36.unipv.it
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↵1 This work was supported in part by a grant from the Italian Ministero dell’Universitá e della Ricerca Scientifica e Tecnologica.
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↵2 Current address: Research Center Sanofi Midy, Via G.B. Piranesi 38, 20137 Italy.
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↵3 Current address: Centre National de la Recherche Scientifique-Molécules Bioactives, Conception, Isolement et Synthèse, URA1843, Faculté de Pharmacie, 5 rue J.B. Clément, 92296 Châtenay-Malabry, France.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine
- MMC
- migrating myoelectrical complex
- MI
- motility index
- Received July 10, 1998.
- Accepted October 15, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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