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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the rat distal colon, 5-hydroxytryptamine (5-HT)-induced Cl- secretion is seen as a rise in short circuit current (Isc). We investigated the 5-HT receptor mediating 5-HT-induced Cl- secretion in the rat distal colon. Rat distal colon was prepared either by stripping away the muscularis propria with the neural ganglia, or by leaving it intact. The tissue was mounted in Ussing chambers and short circuited. 5-HT receptor agonist-induced changes (delta) in Isc were recorded in the presence and absence of 5-HT receptor antagonists. In stripped preparations, the rank order of potency of agonists was: 5-HT > 5-methoxytryptamine > alpha-methyl-5-HT >> 2-methyl-5-HT. 5-HT and 5-methoxytryptamine-induced changes in Isc were antagonized by > or = 0.3 microM tropisetron with pA2 values 6.5 and 6.4, respectively. The 5-HT4 antagonist, SC 53606, antagonized the 5-HT-induced response with a pA2 of 7.2. 5-HT1-like (methysergide), 5-HT1P (N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP)), 5-HT2A (ketanserin) and 5-HT3 (ondansetron) receptor antagonists had no significant effect on the 5-HT response in stripped tissue. 3 microM forskolin, or 10 microM 3-isobutyl-1-methyl-xanthine (IBMX), decreased the EC50 and increased the maximum 5-HT response. The 2-methyl-5-HT and 5-HT-induced delta Isc in the unstripped colon preparation were antagonized by the 5-HT3 antagonist, ondansetron (0.3 nM), and 2-methyl-5-HT activity was abolished by pretreatment with tetrodotoxin. In conclusion, 5-HT-induced delta Isc is neurally mediated via a 5-HT3 receptor, and non-neurally mediated via a 5-HT4 receptor in the rat distal colon.
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PMID:5-Hydroxytryptamine-induced Cl- transport is mediated by 5-HT3 and 5-HT4 receptors in the rat distal colon. 886

The anxiolytic-like effects of a variety of 5-HT receptor agonists and antagonists have been intensively studied in animal models. However, no direct effects of agents modulating 5-HT4 receptors have been reported, in spite of their suggestive location in the brain. The objective of the present study was the determination of the effects of two selective 5-HT4 receptor antagonists, SB 204070 [1-butyl-4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate] and GR 113808 [[1-[2-methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 1-methyl-1 H-indole-3-carboxylate], in the elevated plus-maze test in rats. Results have shown that both 5-HT4 receptor antagonists exhibit an anxiolytic-like profile, although only at the dose of 1.0 mg/kg (s.c.). At this dose, both compounds significantly increased the percentage of time spent in open arms exploration, while other variables evaluated remained unaffected at the dose range tested. Results suggest that 5-HT4 receptor antagonists could have some anxiolytic-like properties, although their effects seem more limited and less consistent than those presented by classic anxiolytics, such as diazepam. However, they are similar to those exhibited by granisetron [endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1 H-indazole-3-carboxamide], a 5-HT3 receptor antagonist.
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PMID:Effects of 5-HT4 receptor antagonists on rat behaviour in the elevated plus-maze test. 887 43

The effects of serotonin (5-hydroxytryptamine) on ventilation were investigated by continuous measurements of intrabuccal pressure in unrestrained eel. Intravenous administration of 5-hydroxytryptamine (30 micrograms.kg-1) caused a large increase in ventilatory frequency (+ 100%) and amplitude (+ 140%). The 5-hydroxytryptamine-induced hyperventilation was blocked by the 5-HT3-receptor antagonists metoclopramide (1.0 mg.kg-1) or MDL72222 (1.0 mg.kg-1), and was insensitive to the 5-HT1/2-receptor antagonist methysergide (3.0 mg.kg-1) and to the 5-HT4-receptor antagonist DAU 6285 CL (3.0 mg.kg-1). The hyperventilatory response to 5-hydroxytryptamine could be mimicked by the 5-HT3 receptor agonist 1-phenylbiguanide (300 micrograms.kg-1). These results strongly implicate the 5-HT3-receptor as the mediator of the 5-hydroxytryptamine-induced hyperventilation in eel.
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PMID:Mediation of serotonin-induced hyperventilation via 5-HT3-receptor in European eel Anguilla anguilla. 888 10

1. Whole-cell patch-clamp recordings were made from 142 visually identified rat dorsal vagal preganglionic neurones (DVMs). Applications of 5-hydroxytryptamine (5-HT, 20 microM, 2 min) elicited a slow depolarization (8.2 +/- 0.5 mV, n = 59) in 95% of the cells tested, accompanied by an increase in excitability. In (68%) of DVMs the depolarization was associated with an increase in apparent membrane resistance (Rmt 22.7 +/- 2.2%). These depolarizations and increases in Rm (14.3 +/- 2.6%, n = 8) were maintained in a medium which blocked synaptic transmission. 2. The response to 5-HT was associated with a reversal potential (Erev) of -91 +/- 1 mV at an extracellular K+ concentration (LK+]o) of 4.2 mM. This correlated well with the K+ equilibrium potential (Ek = -89 mV). 3. The depolarizing effect of 5-HT was attenuated by the 5-HT2A/2C receptor antagonists, ketanserin (1 microM), LY 53,857 (1 microM) and the 5-HT1A/2A receptor antagonist, spiperone (1 microM). The 5-HT1A receptor antagonist, pindobind 5-HT1A (5 microM), had no effect on the depolarizing response to 5-HT. 4. The effect of 5-HT was mimicked by the 5-HT2A/2C receptor agonist, alpha-methyl-5-HT (50 microM), the 5-HT1 receptor agonist, 5-carboxamidotryptamine (20 microM) and the putative 5-HT4 agonist, 5-methyoxytryptamine (5 microM). The selective 5-HT4 receptor antagonist, GR113808, had no effect on the depolarizing effect of 5-HT or 5-MEOT on DVMs. 5. The 5-HT3 antagonists, MDL 72222 (10 microM) and ICS-205-930 (1 and 10 microM), partially reduced the effect of 5-HT. The 5-HT3 receptor agonist, 2-methyl-5-HT (100-300 microM), excited a proportion of neurones tested (56%) by evoking a depolarizing and/or an increase in postsynaptic potentials (p.s.ps). 6. These results are consistent with direct, postsynaptic actions of 5-HT on DVMs via 5-HT2A receptors, being mediated, in part, by the reduction of K+ conductance.
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PMID:The effect of 5-HT and selective 5-HT receptor agonists and antagonists on rat dorsal vagal preganglionic neurones in vitro. 889 72

The effects of chronic infusion with 5-hydroxytryptamine (5-HT, 75 micrograms/kg per hour) for 5 or 10 days in vivo on the responses of rat oesophagus, fundus and jejunum to 5-HT and partial 5-HT receptor agonists in vitro were investigated. In the rat oesophagus, chronic treatment produced rightward shifts of the 5-HT4 receptor-mediated concentration-effect curves to 5-HT (dose-ratio = 3.8, day 5 and 2.8, day 10) and SC 53116 (1-S,8-S)-4-amino-5-chloro-N-[(hexahydro-1H-pyrrolizin-1-yl) methyl]-2-methoxy-benzamide hydrochloride, dose-ratio = 7.1, day 5 and 8.9, day 10) as compared to control tissues. The maximum effect of 5-HT and SC 53116 in rat oesophagus was reduced following the 10 day treatment. The 5-HT2B receptor-mediated contractile effect of 5-HT on rat fundus from treated animals responded with a significantly reduced potency (dose-ratio = 4.1, 5-day; 4.2, 10-day) compared to control tissues. The maximum response to 5-HT was reduced in tissues from animals treated for 10 days. The concentration-effect curve to the partial agonist 1-(3-chlorophenyl)-piperazine dihydrochloride (mCPP) was shifted to the right in fundic tissue from treated animals (dose-ratio = 2.5, 5-day; 2.8, 10-day) compared to control tissues. The maximum response to mCPP was also reduced in tissues from 5-HT treated animals. It has recently been shown in a preliminary characterisation that in rat jejunum, 5-HT produces a biphasic concentration-effect curve which is mediated by a putative 5-ht7 (first phase) and 5-HT3 (second phase) receptor mechanism. In the present study 5-HT produced a control biphasic concentration-effect curve in rat jejunum with a pEC50-1 value of 8.5 +/- 3.5 and a pEC50-2 value of 5.9 +/- 0.3 and maximum response values of 43.8 (32.5-55.0)% (Emax1) and 65.3 (41.7-88.9)% (Emax 2) of the response to acetylcholine. In jejunal tissues from treated animals, 5-HT produced its contractile effect in vitro with a 3.7 and 2.8 fold (5-day) and a 1.3 and 1.4 fold (10-day) rightward shift of the first and second phase respectively of the control concentration-effect curve to 5-HT. The maximum response produced by 5-HT in the first phase in jejunal tissues from animals treated for 10 days was significantly reduced by 49.1%. These findings represent the first report that chronic infusion of 5-HT produces a residual desensitisation of the 5-HT4, 5-HT2B, and putative 5-ht7/5-HT3 receptor-mediated responses in rat oesophagus, fundus and jejunum respectively when measured in vitro.
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PMID:Changes in sensitivity of 5-HT receptor mediated functional responses in the rat oesophagus, fundus and jejunum following chronic infusion with 5-hydroxytryptamine. 889 56

The possibility that 5-hydroxytryptamine (5-HT) acts as a key sensitising agent in the aetiology of irritable bowel syndrome (IBS) is reviewed. The strategic locations of 5-HT and its receptors are described, the most dominant being the 5-HT3 and 5-HT4 type. 5-HT, acting mostly at 5-HT3 or 5-HT3-like receptors, enhances the sensitivity of visceral neurones projecting between the gut and the central nervous systems. 5-HT, acting at 5-HT4 receptors promotes the sensitivity of enteric neurones that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitising and physiological actions of 5-HT on gastro-intestinal motor and secretory functions. This distribution implies that some 5-HT3 receptor antagonists might reduce certain symptoms of IBS, such as pain, by reducing the reactivity of the visceral afferent neurones linking the gut with the brain and spinal cord. However, such antagonists are not likely to find widespread clinical acceptance because they can also affect normal lower bowel function and promote constipation. 5-HT4 receptor antagonists, by contrast, reduce 5-HT-induced enteric nerve hypersensitivity without notably affecting the function of the normal bowel. Accordingly, these agents may reduce the symptoms of IBS directly, by reducing the incidence of defecation and diarrhoea and indirectly, by reducing both 'rebound' constipation and the post-prandial discomfort and pain associated with gastrointestinal hyper-reactivity.
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PMID:5-Hydroxytryptamine and functional bowel disorders. 895 36

1. Although conscious dogs have often been used for colonic motility studies with 5-hydroxytryptamine (5-HT), the effects of 5-HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5-HT of the canine isolated colon longitudinal muscle. 2. Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5-HT induced contractions from 3 nM onwards, which were not affected by selective inhibition of 5-HT re-uptake, monoamine oxidase or blockade of alpha-adrenoceptors. Tetrodotoxin (0.3 microM) did not affect the responses to 5-HT, suggesting that smooth muscle 5-HT receptors are involved. The selective 5-HT4 receptor antagonist SB 204070 (10 nM) slightly enhanced contractions to 5-HT and therefore it was included in the organ bath solution in all further experiments. The 5-HT1 and 5-HT2 receptor antagonist methysergide (0.1 microM) depressed the curve to 5-HT, but the selective 5-HT3 receptor antagonist granisetron (0.3 microM) had no effect. 3. Besides 5-HT, alpha-methyl-5-HT (alpha-Me-5-HT), 5-methoxytryptamine (5-MeOT), 2-methyl-5-HT (2-Me-5-HT) and 5-carboxamidotryptamine (5-CT) also induced contractions, with the following rank order of potency (pEC50 values in parentheses): 5-HT (6.9) = alpha-methyl-5-HT (6.9) > 2-Me-5-HT (5.8) = 5-MeOT (5.7) = 5-CT (5.6), indicative of 5-HT2 receptor involvement, alpha-Me-5-HT produced a bell-shaped curve, which was not affected by alpha-adrenoceptor blockade. 5-HT, 5-MeOT, 2-Me-5-HT and 5-CT produced a monophasic concentration-response curve, consistent with an interaction with a single receptor site. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and tryptamine only induced contractions at a concentration exceeding 1 microM. 4. The selective 5-HT2B receptor antagonist SB 204741 (0.3 microM) did not affect the curve to 5-HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with pKb values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1 microM) shifted the curve to 5-MeOT rightward yielding an apparent pA2 of 7.1. Other antagonists at 5-HT2A receptors also surmountably inhibited the contractions to 5-HT (apparent pA2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of "pseudo-irreversible' antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5-HT2A receptors. 5. It was concluded that 5-HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5-HT2A receptors. The presence of inhibitory 5-HT4 receptors cannot be ruled out.
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PMID:Characterization of the contraction to 5-HT in the canine colon longitudinal muscle. 905 13

We investigated the effects of ramosetron (YM060, (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) on the short-circuit current (Isc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT3 receptor antagonists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased Isc. The Isc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 ([[1-[(2-methyl-sulphonyl) amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1 H-indole-3-carboxylate). 2-Methyl-5-HT and 5-methoxytryptamine also increased Isc. The former response was inhibited by ramosetron, and the latter was abolished by GR113808. Ramosetron, YM114 (KAE-393, (-)-(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) and granisetron concentration-dependently antagonized the Isc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.40, 10.37 and 8.99, respectively. Ondansetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA2 value of 8.53. These results suggest that 5-HT increases Isc through the 5-HT3 and 5-HT4 receptors, and that ramosetron is a potent and selective 5-HT3 receptor antagonist in rat colonic mucosa.
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PMID:Effect of ramosetron on short-circuit current response in rat colonic mucosa. 905 53

We have already reported that 5-hydroxytryptamine3 (5-HT3) receptor antagonists failed to modify 5-HT-accelerated colonic transit in conscious rats, but the 5-HT3 and 5-HT4 receptor dual antagonist FK1052 prevented the enhancement. In this study, the inhibitory effect on the stimulated colonic transit was not also observed with 5-HT4 receptor antagonists (SDZ205-557 and SB204070) in freely moving rats with chronic cannulas implanted into the proximal colon. In contrast, combined antagonism by simultaneous administration of ondansetron and the 5-HT4 receptor antagonist exerted a drastic inhibitory effect on the propulsive motility. Furthermore, we examined the effect of 5-HT receptor antagonists on 5-HT-induced fluid secretion in mice. Although none of these selective 5-HT receptor antagonists (YM060 and ondansetron as 5-HT3 receptor antagonist, SB204070 as 5-HT4 receptor antagonist) by itself produced a great inhibition of the 5-HT-induced diarrhea, the combination of a 5-HT3 receptor antagonist and a 5-HT4 receptor antagonist markedly reduced the diarrhea. These data suggest that 5-HT-accelerated colonic motility and 5-HT-evoked fluid secretion are mediated by both 5-HT3 and 5-HT4 receptors and that the pathways activated by these receptors may collaborate.
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PMID:Combined blockade of 5-HT3- and 5-HT4-serotonin receptors inhibits colonic functions in conscious rats and mice. 910 8

GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadiazol-3-yl) [1, 1-biphenyl]-4-carboxamide hydrochloride) has been recently introduced as an experimental tool to antagonize 5-HT(1B/D) receptor-mediated functional responses. The compound indeed exhibits a very high affinity and selectivity for 5-HT(1B/D) binding sites and it antagonizes a number of 5-HT(1B/D) receptor-mediated responses. The present experiments were performed to investigate the selectivity of GR127935 against functional responses mediated by 5-HT1-like, 'orphan' 5-HT1-like (5-ht7?), 5-HT2, 5-HT3 or 5-HT4 receptors in several in vivo preparations. Intravenous (i.v.) treatment with GR127935 (300 microg x kg(-1)) potently antagonized decreases in total carotid blood flow as well as hypotensive responses induced by the 5-HT1-like receptor agonist sumatriptan in rabbits. I.v. bolus injections of GR127935 (up to 500 and/or 1500 microg x kg(-1)) did not significantly modify 5-HT-induced: (i) tachycardia in the pig (5-HT4 receptor-mediated) and cat ('orphan' 5-HT1-like or, perhaps, 5-ht7 receptor-mediated); (ii) depressor effects in the rat and cat ('orphan' 5-HT1-like or 5-ht7 receptor-mediated); (iii) von Bezold-Jarisch reflex in the rat or the early phase of the urinary bladder contraction in the cat (both 5-HT3 receptor-mediated). In contrast, high doses (500-1500 microg x kg(-1)) of GR127935 suppressed 5-HT-induced pressor responses in the rat and cat and urinary bladder contractions (secondary phase) in the cat as well as the DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride)-induced pressor responses in the rat, which are all mediated by 5-HT2A receptors. In conclusion, the present study demonstrates that GR127935 is a selective 5-HT(1B/D) receptor antagonist devoid of interactions at 'orphan' 5-HT1-like (5-ht7?), 5-HT3 and 5-HT4 receptors. However, GR127935 possesses a moderate 5-HT2A receptor blocking property, which is consistent with its binding profile (pKi: 7.4). Lastly, in view of the potent antagonist action of GR127935, the sumatriptan-induced hypotension in rabbits seems to be mediated by 5-HT(1B/D) receptors.
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PMID:Interactions of GR127935, a 5-HT(1B/D) receptor ligand, with functional 5-HT receptors. 910 56


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