Evidence against an acetylcholine releasing action of cisapride in the human colon.

De, Biswanath; Trout, SJ

doi:10.1111/j.1365-2125.1985.tb05100.x

Cited by 21 publications

(7 citation statements)

References 7 publications

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“…Our study thus shows that in human colon, excitatory 5-HT 4 receptors are present on cholinergic nerves within the CM layer, similar to those shown before on the cholinergic nerves within the longitudinal muscle layer. 9 The non-effect of cisapride on electrically induced acetylcholine release in human colonic taenial longitudinal muscle reported earlier 16 is probably due to the partial agonist effect of cisapride on 5-HT 4 receptors being insufficient to enhance acetylcholine release from cholinergic nerves. The presence of excitatory 5-HT 4 receptors on cholinergic nerve endings in human colon CM, and longitudinal muscle 9 contrasts with findings in longitudinally mounted guinea-pig colon segments, suggesting that 5-HT 4 receptors are primarily located on the soma of intrinsic motor neurones.…”

Section: Discussionmentioning

confidence: 93%

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

Leclere

Prins

Schuurkes

et al. 2005

Neurogastroenterology Motil

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5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called 'whole tissue' strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in 'isolated' CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 micromol L-1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon.

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Section: Discussionmentioning

confidence: 93%

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

Leclere

Prins

Schuurkes

et al. 2005

Neurogastroenterology Motil

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“…It was even suggested that a 5-HT 4 receptor-mediated mechanism of release of acetylcholine was absent in the human colon, on basis of the observation that the 5-HT 4 receptor agonist cisapride failed to modify unstimulated or EFS-stimulated release of 3 H-acetylcholine from human colonic taenial muscle (Burleigh & Trout, 1985). Interestingly, the endogenous ligand 5-HT was not tested in that study.…”

Section: Discussionmentioning

confidence: 94%

5‐HT₄ receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Prins

Akkermans

Lefebvre

et al. 2000

British J Pharmacology

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1 5-HT 4 receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5-HT 4 receptor agonists in vivo. We set out to characterize 5-HT 4 receptor-mediated e ects in longitudinal muscle strips of canine and human large intestine. 2 Electrical ®eld stimulation (EFS) was applied providing submaximal isotonic contractions. L-NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide-induced relaxation to EFS. 3 The selective 5-HT 4 receptor agonist prucalopride (0.3 mM) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT 4 receptor antagonist GR 113808 (0.1 mM). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional di erences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 mM) or tetrodotoxin (0.3 mM) inhibited EFS-induced contractions, which were then una ected by prucalopride (0.3 mM) in both tissues. 4 In the presence of methysergide (3 mM; both tissues) and granisetron (0.3 mM; only human tissues), 5-HT (0.3 mM) enhanced EFS-induced contractions, an e ect that was antagonized by GR 113808 (0.1 mM). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 mM) ine ective in both preparations. 5 This study demonstrates for the ®rst time that in human and canine large intestine, 5-HT 4 receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5-HT 4 receptor agonism facilitates colonic propulsion via a coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility.

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“…41 Prokinesia may result from increased release of acetylcholine (and tachykinins) from excitatory neurones and may operate in human small bowel and stomach, 103 104 but early investigations failed to identify this pathway in human colonic circular muscle. 105 An in vivo study in dogs showed that tachykininergic pathways play an important role in mediating the colonic motor response to administration of the 5-HT 4 receptor agonist ML10302 whereas they are not involved in ML10302 induced prokinesia in the small bowel. 106 Besides these actions, 5-HT 4 receptors also affect secretory processes at the mucosal level.…”

Section: -Ht 3 Receptor Agonists In Therapeutics: Preliminary Evidencementioning

confidence: 99%

Pharmacology of serotonin: what a clinician should know

Ponti

2004

Gut

130

102

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SUMMARYThe pharmacology of serotonin (5-hydroxytryptamine or 5-HT) in the gut has been the centre of intense interest and research for several decades. Although it is now recognised that 5-HT is contained in intrinsic enteric neurones (where it works as a neurotransmitter), enterochromaffin cells of the mucosa are the main source (more than 90%) of the body's 5-HT. In the gut, 5-HT is an important mucosal signalling molecule targeting enterocytes, smooth muscle cells, and enteric neurones. Application of exogenous 5-HT evokes so many responses that it is difficult to determine which are physiologically relevant. This bewildering range of effects is largely due to the presence of multiple receptor subtypes, which appear to be present on several classes of myenteric neurones, on smooth muscle cells, and on epithelial cells. 5-HT is thought to be involved in the pathophysiology of several clinical entities such as functional gut disorders (namely, irritable bowel syndrome), carcinoid diarrhoea, and chemotherapy induced emesis. In this review, the possible targets for pharmacological intervention are analysed in the light of the most recent advances of our understanding of the role of 5-HT in gut pathophysiology. Indeed, the recent regulatory interventions on cisapride (a 5-HT 4 receptor partial agonist) and alosetron (a 5-HT 3 receptor antagonist) have prompted a rethinking of our approaches to the pharmacological modulation of serotonergic pathways. In gut disorders, the most interesting targets for pharmacological intervention are: (1) the 5-HT receptor subtypes known to affect gut function such as those belonging to the 5-HT 1 , 5-HT 3 , 5-HT 4 , and 5-HT 7 subtypes; and (2) the 5-HT reuptake mechanism which, apart from the central nervous system, is expressed in enteric neurones and enterocytes and is blocked by antidepressants.

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Evidence against an acetylcholine releasing action of cisapride in the human colon.

Cited by 21 publications

References 7 publications

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

5‐HT₄ receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Pharmacology of serotonin: what a clinician should know

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Evidence against an acetylcholine releasing action of cisapride in the human colon.

Cited by 21 publications

References 7 publications

5‐HT4 receptors located on cholinergic nerves in human colon circular muscle

5‐HT4 receptors located on cholinergic nerves in human colon circular muscle

5‐HT4 receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Pharmacology of serotonin: what a clinician should know

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Product

Resources

About

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

5‐HT₄ receptors located on cholinergic nerves in human colon circular muscle

5‐HT₄ receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle