Pharmacological characterization of the 5‐HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle

Janssen, Pieter; Prins, Nh; Meulemans, A.L.; Lefebvre, Romain

doi:10.1038/sj.bjp.0704716

Cited by 40 publications

(36 citation statements)

References 25 publications

(28 reference statements)

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“…However, platelet-activating factor (PAF)-induced corporal contractions were blocked by methysergide, indicating the involvement of 5-HT in the rat corporal contraction. 35) Janssen et al 36,37) have shown the mediation of contractions in canine and porcine proximal stomach longitudinal smooth muscles to involve 5-HT 2A receptors, which is consistent with the present results. On the other hand, in guinea pig corpus, 5-HT caused relaxations that were mediated via 5-HT 1 receptors.…”

Section: Discussionsupporting

confidence: 93%

Pharmacological Characterization of 5-Hydroxytryptamine-Receptor Subtypes in Circular Muscle from the Rat Stomach

Komada

Yano

2007

Biological & Pharmaceutical Bulletin

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It is generally accepted that gastric emptying is regulated by the coordination of the proximal and distal stomach motilities. 5-HT has proven to be an important mediator of gastrointestinal motility.1,2) The stimulation of 5-HT 1B/1D receptors induces gastric accommodation in humans 3) and dogs, 4) and delays gastric emptying in humans. 5,6) The blockade of 5-HT 3 receptors inhibits gastrointestinal motility in humans. 7) In addition, the stimulation of 5-HT 4 receptors elicits gastrointestinal contractile activity and increases the rate of gastric emptying in humans 8,9) and dogs. [10][11][12] With regard to gastric smooth muscle activity, it is generally accepted that the 5-HT 1B/1D and 5-HT 7 receptors are relaxant whereas the 5-HT 2 , 5-HT 3 and 5-HT 4 receptors are contractile. Although the gastric contractility of 5-HT has been reported in a variety of species and stomach regions, regional and functional differences of 5-HT-receptor subtypes have been fully investigated only in the guinea pig stomach. [13][14][15][16] In the guinea pig stomach, the fundus presents the relaxant 5-HT 1 receptors and the contractile 5-HT 2 and 5-HT 3 receptors, the corpus presents the relaxant 5-HT 1 receptors and the contractile 5-HT 3 and 5-HT 4 receptors, and the antrum presents the contractile 5-HT 2 , 5-HT 3 and 5-HT 4 receptors. However, the in vivo studies for examining gastric motility and gastric emptying using guinea pigs are limited. On the other hand, the rat is widely used as in vivo models to study gastric motility [17][18][19] and gastric emptying rate. [20][21][22] The stimulation of 5-HT 2 receptors increases gastric motility, 17) the blockade of 5-HT 3 receptors accelerates gastric emptying, 20) and the stimulation of 5-HT 4 receptors increases gastric motility 18) and accelerates gastric emptying. 20,21) In in vitro, pharmacological characterization of the contractile response to 5-HT in the rat stomach regions still remains unclear, except for the contractile 5-HT 2B receptors in longitudinal muscle strips of the fundus. [23][24][25] The present study was, therefore, designed to provide further information regarding functions of 5-HT receptor subtypes in circular muscle strips from the antrum, corpus and fundus of the rat stomach. MATERIALS AND METHODSChemicals Carbachol (CCh), atropine sulfate monohydrate and tetrodotoxin (TTX) were purchased from Wako Pure Chemicals (Osaka, Japan). 5-Hydroxytryptamine hydrochloride (5-HT), methysergide maleate, ketanserin tartrate and SB-269970 (selective 5-HT 7 receptor antagonist) were purchased from Sigma (St. Louis, MO, U.S.A.). WAY-100635 maleate (selective 5-HT 1A receptor antagonist), GR127935 hydrochloride (5-HT 1B/1D receptor antagonist) and cinanserin hydrochloride (selective 5-HT 2 receptor antagonist) were purchased from Tocris Cookson (Ellisville, MO, U.S.A.). RS-127445 (selective 5-HT 2B receptor antagonist), ondansetron (selective 5-HT 3 receptor antagonist) and SB-203186 (selective 5-HT 4 receptor antagonist) were synthesized at Pfizer Inc. All the drugs...

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Section: Discussionsupporting

confidence: 93%

Pharmacological Characterization of 5-Hydroxytryptamine-Receptor Subtypes in Circular Muscle from the Rat Stomach

Komada

Yano

2007

Biological & Pharmaceutical Bulletin

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“…For example, in the rat fundus, 5-HT contracts the fundus through 5-HT 1 receptors but not 5-HT 2 receptors (8). In the canine fundus, the predominant contractile effect of 5-HT is mediated by 5-HT 2A receptors (17).…”

Section: Discussionmentioning

confidence: 99%

Serotonergic modulation of murine fundic tone

Lü

Camilleri²,

Locke³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fundic tone is maintained through a balance of excitatory and inhibitory input to fundic smooth muscle. The aim of this study was to determine the role of serotonin (5-HT) and 5-HT receptors in modulating murine fundic tone. Muscle strips were prepared from the murine fundus. Intracellular recordings were made from circular smooth muscle cells, and the effects of 5-HT on tone and excitatory and inhibitory junction potentials evoked by electrical field stimulation (EFS) were determined. 5-HT induced a concentration-dependent contraction and smooth muscle depolarization that was tetrodotoxin resistant. The 5-HT 1B/D receptor antagonists GR-127935 and BRL-155172 significantly inhibited 5-HT-induced contractions. The 5-HT 1B/D agonist sumatriptan contracted murine fundic muscle. The 5-HT 1A receptor agonist buspirone relaxed fundic smooth muscle, and the relaxation was inhibited by WAY-100135 but not by N -nitro-L-arginine or tetrodotoxin. 5-HT enhanced both the excitatory and inhibitory responses to EFS. The 5-HT 3 receptor antagonist MDL-72222 partly inhibited both the excitatory and inhibitory response elicited by EFS, whereas the 5-HT 4 receptor antagonist GR-113808 partly inhibited the EFS-evoked inhibitory response. The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR-127935 and abolished by tetrodotoxin. In conclusion, the data suggest that 5-HT modulates murine fundic contractile activity through several different receptor subtypes. Sustained release of 5-HT maintains fundic tone through postjunctional 5-HT 1B/D receptors. 5-HT 3 receptors modulate excitatory neural input to murine fundic smooth muscle, and both 5-HT 3 and 5-HT4 receptors modulate inhibitory neural input to murine fundic smooth muscle.receptors; smooth muscle; enteric nerves; fundic accommodation; serotonin THE STOMACH WALL relaxes to accommodate the entry of content. Relaxation allows the accommodation of a large volume of content without a marked increase in intragastric pressure (7,15). Although there is evidence that the antrum accommodates after a meal, gastric accommodation occurs predominantly in the proximal stomach, especially in the fundus. The fundic integrated relaxatory response to a meal is known as fundic accommodation. The accommodation response is mediated through an extrinsic vagovagal reflex pathway and a nonvagal intrinsic reflex pathway. Both pathways act on intrinsic noncholinergic, nonadrenergic (NANC) neurons in the fundus and other parts of the stomach wall to relax smooth muscle cells (1,3,26,28). In the fasted state, well-established mediators of gastric fundic tone are vagally mediated cholinergic input (2, 29) and NANC inhibitory input (11, 12). The regulation of fundic tone is also mediated through serotonin (5-HT). In humans, sumatriptan, a 5-HT 1B/D agonist, relaxes the fundus (24, 25). In mice, in vivo, buspirone relaxed the fundus, whereas sumatriptan contracted it (29). There are two sources for 5-HT in the gut: release from enterochromaffi...

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“…In the gut, studies have shown that 5-HT induces muscle relaxation by affecting 5-HT 7 receptors on smooth muscle cells in addition to neuronal 5-HT 7 receptors (55)(56)(57)(58). Although the effects of selective 5-HT 7 antagonism have been studied in several animal behavioral models where it has been shown to have anxiolytic (59-61), antidepressant (62)(63)(64), and antipsychotic-like effects (65,66), to our knowledge, no current data are available on the effects of 5-HT 7 receptor antagonists in IBD.…”

Section: Cd11cmentioning

confidence: 99%

Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation

Kim

Bridle

Ghia

et al. 2013

The Journal of Immunology

108

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Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7−/−) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7−/− mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7−/− mice and in mice reconstituted with bone marrow cells from 5-HT7−/− mice compared with control mice after DSS colitis. 5-HT7−/− mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

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Pharmacological characterization of the 5‐HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle

Cited by 40 publications

References 25 publications

Pharmacological Characterization of 5-Hydroxytryptamine-Receptor Subtypes in Circular Muscle from the Rat Stomach

Pharmacological Characterization of 5-Hydroxytryptamine-Receptor Subtypes in Circular Muscle from the Rat Stomach

Serotonergic modulation of murine fundic tone

Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation

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