Luminal 5‐HT<sub>4</sub> receptors—A successful target for prokinetic actions

Gwynne, Rachel M; Bornstein, Joel C.

doi:10.1111/nmo.13708

Cited by 15 publications

(25 citation statements)

References 110 publications

(243 reference statements)

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“…37 In conclusion, the concept that activation of luminal 5-HT 4 receptors could provide a safe and effective approach for the treatment of constipation is gaining momentum. 22 The findings described here reveal that novel, luminally acting 5-HT 4 R agonist compounds can generate prokinetic actions in the colon. This further supports effort to selectively target the epithelium within GI tract to generate safe and effective therapies for constipation by avoiding systemic side effects.…”

Section: Discussionmentioning

confidence: 72%

“…19 Therefore, the concept of targeting luminal 5-HT 4 receptors to alleviate constipation is gaining momentum. 22 In the present study, we tested the hypothesis that 5-HT 4 R agonists that are designed to act within the lumen, with minimal absorption and systemic distribution, could elicit prokinetic actions. In these experiments, we used assays that have been previously described in mice to evaluate the actions of these agents both in vivo and ex vivo, [23][24][25] and we used immunofluorescence to evaluate 5-HT 4 R expression in human intestinal epithelium.…”

Section: -Ht 4 R Agonists Have Prokinetic Actions and As A Result mentioning

confidence: 99%

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Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Konen

Haag

Guseva

et al. 2020

Neurogastroenterology Motil

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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.

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Section: Discussionmentioning

confidence: 72%

Section: -Ht 4 R Agonists Have Prokinetic Actions and As A Result mentioning

confidence: 99%

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Konen

Haag

Guseva

et al. 2020

Neurogastroenterology Motil

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“…This indicates that 5-HT receptor-mediated mechanisms may play a role in the minute rhythm motor pattern. 5-HT receptors are prominent on enteric neurons ( Keating and Spencer, 2019 ; Spencer and Hu, 2020 ) in the gut mucosa ( Gwynne and Bornstein, 2019 ; Shokrollahi et al, 2019 ) and in the brain ( Browning and Travagli, 2014 ; Browning, 2015 ) and play multiple roles in the physiology and pharmacology of intestinal propulsive motor patterns ( Gershon, 2004 ; Bornstein, 2012 ; Gershon, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Parsons

Huizinga

2021

Front. Neurosci.

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Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4–8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP.

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“…Studies using the isolated rabbit colon showed that prucalopride could stimulate propulsive contractions when administered directly into the colonic lumen. 50,51 Results from a Phase 3 clinical trial revealed that prucalopride was effective in treating chronic constipation by stimulating at least 3 bowel movements per week. 52 This is relevant to the study by Previous studies used guinea pigs and rats to assess colonic motility and secretion and to test for visceral hypersensitivity.…”

Section: Entero Chromaffin(ec)cellsmentioning

confidence: 99%

Colonic 5‐HT₄ receptors are targets for novel prokinetic drugs

Galligan

2021

Neurogastroenterology Motil

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5-HT 4 receptors are G protein-coupled receptors that link to the stimulatory protein Gs which activates adenylate cyclase to increase intracellular cyclic AMP which then activates protein kinase A (PKA). 5-HT 4 receptors are expressed by neurons in the central and peripheral nervous systems especially the enteric nervous system (ENS). In general, 5-HT 4 receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5-HT 4 receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of Neurogastroenterology and Motility features two novel 5-HT 4 receptor agonists (5-HT 4-LA1 and 5-HT 4-LA-2) that are not absorbed from the gastrointestinal tract of mice and act locally in the colonic mucosa to stimulate propulsive motility. The authors show that 5-HT 4-LA1 and 5-HT 4-LA2 were not absorbed from the colon and that both drugs stimulated colonic transit when administered by gavage. Both agonists stimulated colonic glass bead expulsion, and 5-HT 4 LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5-HT 4 receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5-HT 4 receptor agonists that have prokinetic actions on the GI tract. These drugs are not absorbed and act locally in the gut mucosa to stimulate propulsive motility while minimizing access to systemic 5-HT 4 receptors and avoiding potential unwanted side effects. K E Y W O R D S 5-HT 4 receptors, colon motility, prokinetic drugs KeyPoints • Irritable bowel syndrome-constipation (IBS-C) and chronic constipation are two common gastrointestinal motility disorders. There are no universal treatments that reliably treat constipation and that are without side effects. Howtocitethisarticle:Galligan JJ. Colonic 5-HT 4 receptors are targets for novel prokinetic drugs. Neurogastroenterology &

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Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Cited by 15 publications

References 110 publications

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Colonic 5‐HT₄ receptors are targets for novel prokinetic drugs

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Luminal 5‐HT4 receptors—A successful target for prokinetic actions

Cited by 15 publications

References 110 publications

Prokinetic actions of luminally acting 5‐HT4 receptor agonists

Prokinetic actions of luminally acting 5‐HT4 receptor agonists

Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP

Colonic 5‐HT4 receptors are targets for novel prokinetic drugs

Contact Info

Product

Resources

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Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

Colonic 5‐HT₄ receptors are targets for novel prokinetic drugs