Prokinetic actions of luminally acting 5-HT 4 receptor agonists.

Autor: Konen JR; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA.; Department of Surgery, University of Vermont Medical Center, Burlington, VT, USA., Haag MM; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA., Guseva D; Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany., Hurd M; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA., Linton AA; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA., Lavoie B; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA., Kerrigan CB; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA.; Department of Surgery, University of Vermont Medical Center, Burlington, VT, USA., Joyce E; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA., Bischoff SC; Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany., Swann S; Takeda Pharmaceutical Company, San Diego, CA, USA., Griffin L; Takeda Pharmaceutical Company, San Diego, CA, USA., Matsukawa J; Takeda Pharmaceutical Company, San Diego, CA, USA., Falk MD; Takeda Pharmaceutical Company, San Diego, CA, USA., Gibson TS; Takeda Pharmaceutical Company, San Diego, CA, USA., Hennig GW; Department of Pharmacology, University of Vermont, Burlington, VT, USA., Wykosky J; Takeda Pharmaceutical Company, San Diego, CA, USA., Mawe GM; Department of Neurological Sciences, University of Vermont, Burlington, VT, USA.; Department of Pharmacology, University of Vermont, Burlington, VT, USA.
Jazyk: angličtina
Zdroj: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society [Neurogastroenterol Motil] 2021 Apr; Vol. 33 (4), pp. e14026. Date of Electronic Publication: 2020 Nov 12.
DOI: 10.1111/nmo.14026
Abstrakt: 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.
(© 2020 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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