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Prokinetic actions of luminally acting 5‐HT 4 receptor agonists
Author(s) -
Konen John R.,
Haag Melody M.,
Guseva Daria,
Hurd Molly,
Linton Alisha A.,
Lavoie Brigitte,
Kerrigan Colleen B.,
Joyce Emily,
Bischoff Stephan C.,
Swann Steve,
Griffin Luana,
Matsukawa Jun,
Falk Matthew D.,
Gibson Tony S.,
Hennig Grant W.,
Wykosky Jill,
Mawe Gary M.
Publication year - 2021
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.14026
Subject(s) - 5 ht4 receptor , motility , agonist , ex vivo , in vivo , stimulation , prokinetic agent , tegaserod , biology , medicine , receptor antagonist , receptor , pharmacology , endocrinology , antagonist , irritable bowel syndrome , microbiology and biotechnology
Background 5‐HT 4 receptor (5‐HT 4 R) agonists exert prokinetic actions in the GI tract, but non‐selective actions and potential for stimulation of non‐target 5‐HT 4 Rs have limited their use. Since 5‐HT 4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5‐HT 4 R agonists promote intestinal motility. Methods Non‐absorbed 5‐HT 4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5‐HT 4 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‐HT 4 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‐HT 4 R antagonist and were not detected in 5‐HT 4 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‐HT 4 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‐HT 4 Rs can potentiate propulsive motility and support the concept that mucosal 5‐HT 4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.