Prokinetic actions of luminally acting 5‐HT 4 receptor agonists
| Autor: | Melody M. Haag, Emily J. Joyce, Jun Matsukawa, Brigitte Lavoie, Grant W. Hennig, Luana Griffin, Colleen B. Kerrigan, Steve Swann, Alisha A. Linton, Jill Wykosky, Molly C. Hurd, Matthew D. Falk, Gary M. Mawe, Stephan C. Bischoff, John R. Konen, Daria Guseva, Tony Gibson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist Prucalopride Endocrine and Autonomic Systems Physiology medicine.drug_class business.industry Gastroenterology 5-HT4 receptor Motility Stimulation Pharmacology musculoskeletal system 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Intestinal mucosa In vivo medicine 030211 gastroenterology & hepatology business Ex vivo medicine.drug |
| Zdroj: | Neurogastroenterology & Motility. 33 |
| ISSN: | 1365-2982 1350-1925 |
| DOI: | 10.1111/nmo.14026 |
| Popis: | BACKGROUND 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation. |
| Databáze: | OpenAIRE |
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