Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cisapride on intestinal contractility and on release of acetylcholine (ACh) were examined using the longitudinal muscle with the myenteric plexus preparation from the guinea pig ileum, as related to the 5-hydoxytryptamine (5-HT) receptor. 5-HT exerted a dual effect, transient increase in ACh release (EC50 = 2 X 10(-6)M) via the 5-HT3 receptor, followed by inhibition (EC50 = 5 X 10(-9)M) via the 5-HT1 receptor. Cisapride at low concentrations (10(-9)M to 10(-8)M) enhanced electrical stimulation -evoked contraction and ACh release. The effect of cisapride was mimicked by methysergide and was not altered by ICS 205-930. Cisapride antagonized the 5-HT (5 X 10(-9) M)-induced inhibitory effect and the IC50 of cisapride was 1.5 X 10(-9) M. These findings indicate that enhancement by low concentrations of cisapride may be due to a block of the inhibitory 5-HT1 receptor. Cisapride at medium concentrations (10(-8) M to 3 X 10(-7) M) induced enhancement of electrical stimulation-evoked twitch contractions and ACh release evoked by electrical stimulation which were antagonized by 10(-6) M ICS 205-930, while this compound antagonized the 5-HT (2 X 10(-6) M)-and 2-methyl-5-HT-induced excitatory effects, and the IC50 of cisapride was 5.2 X 10(-8) M. Thus, cisapride acts on the putative 5-HT4 receptor as an agonist and the 5-HT3 receptor as an antagonist. Cisapride at high concentrations (10(-6) M to 10(-5) M) evoked contraction and the release of ACh, and these effects were antagonized by ICS 205-930 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cisapride stimulates motility of the intestine via the 5-hydroxytryptamine receptors. 189 Jun 14

Whereas opiate receptor antagonists generally act to inhibit food intake under a variety of physiological conditions in rats, agonists of some serotonin (5-HT) receptor subtypes appear to stimulate intake, and others appear to inhibit intake. The present study evaluated the effects of the general 5-HT receptor antagonist, methysergide (1-5 mg/kg), the 5-HT2 receptor antagonists, ketanserin (1-2.5 mg/kg) and ritanserin (1-2.5 mg/kg), and the 5-HT3 receptor antagonist, ICS 205930 (1-5 mg/kg) upon deprivation (24 h)-induced intake themselves, and upon the hypophagic properties of the general opiate receptor antagonist, naloxone (1-5 mg/kg). Whereas the high doses of methysergide (0.5-4 h, 34%) and ketanserin (0.5 h, 28%) significantly decreased deprivation-induced intake themselves, ritanserin and ICS 205930 were without effect. Naloxone produced dose-dependent reductions in deprivation-induced intake (24-45%). Methysergide (1 mg/kg) significantly potentiated naloxone (5 mg/kg) hypophagia after 0.5 h. Significant potentiations of hypophagia occurred following pairing the 1 mg/kg ketanserin dose with the 1 and 5 mg/kg naloxone doses at 2 and 4 h respectively, and pairing the 2.5 mg/kg ketanserin and 1 mg/kg naloxone doses at 0.5 and 2 h. Whereas the 1 mg/kg dose of ritanserin eliminated naloxone (1 mg/kg) hypophagia over a 2-h time course, ritanserin failed to exert further effects in other dose conditions. The differences between ketanserin and ritanserin in their effects upon deprivation-induced feeding and naloxone hypophagia suggest that the former's antagonistic actions upon alpha-adrenergic receptors may be responsible for its effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Naloxone and serotonin receptor subtype antagonists: interactive effects upon deprivation-induced intake. 190 86

1. The effects of 5-hydroxytryptamine (5-HT) on the release of cholexystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2. In both areas 5-HT, tested between 0.1 and 100 nM, increased the calcium-dependent, depolarization-evoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 +/- 0.045 nM and 0.48 +/- 0.053 nM, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nM 5-HT). 3. The 5-HT1/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10 nM 5-HT. However, the effects of 10 nM 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930; 0.1-100 nM; IC50: 3.56 +/- 0.42 nM in the cortex and 3.90 +/- 0.50 nM in the n. accumbens) and ondasetron (IC50: 8.15 +/- 0.73 nM in the cerebral cortex). 5-HT (10 nM) was also strongly antagonized by 100 nM 1 alpha H, 3 alpha 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 +/- 0.071 nM). 4. It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs.
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PMID:Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens. 193 41

Both acetylcholine (ACh) and serotonin (5-HT) lowered the serosa-negative transepithelial potential difference (PD) and the short-circuit current (Isc), accompanied by a decrease in NaCl and water absorption across the eel intestine. These inhibitory effects of ACh and 5-HT were blocked by atropine, a muscarinic receptor antagonist, and ICS-205930, a 5-HT3 receptor antagonist, respectively. Even after blocking the ACh receptor with atropine, 5-HT inhibited the PD and Isc, and ACh lowered them after blocking the 5-HT receptor with ICS-205930, indicating that ACh and 5-HT act independently. Similar inhibition in the PD and the Isc was observed after electrical field stimulation (EFS) which is expected to release endogenous regulators. These effects of EFS were reduced by 70% after simultaneous addition of atropine and ICS-205930. Since atropine and ICS-205930 block ACh and 5-HT receptors, respectively, these results suggest that endogenous ACh and 5-HT are released by EFS.
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PMID:Regulation of ion and water transport across the eel intestine: effects of acetylcholine and serotonin. 193 45

Serotonin (5-HT) receptors in the myenteric plexus mediate contractility in vitro and may regulate gastric emptying in vivo. This report examines the pharmacology of three benzamides, ML-1035 (4-amino-5-chloro-2-[2-(methylsulfinyl)-ethoxy]-N-[2- (diethylamino)ethyl]-benzamide hydrochloride), metoclopramide and cisapride, in studies which address the serotonergic mechanisms underlying benzamide-induced gastroprokinesis. All three compounds had high affinity at the 5-HT3 receptor as they displaced the 5-HT3 antagonist [3H]GR65630 from cortical membranes (Ki = 156, 232 and 1711 nM for ML-1035, metoclopramide and cisapride, respectively) and blocked the 5-HT-induced Bezold-Jarisch reflex, although cisapride was much less active in this experiment. Receptor selectivity was also compared at 5-HT1, 5-HT2, and dopamine D2 receptors in which no displacement was observed that was common to all agents. All benzamides elicited a 5-HT4-like agonist response as they enhanced field-stimulated neurogenic contractions in ileum (EC50 = 1.4, 1.6 and 0.013 microM for ML-1035, metoclopramide and cisapride, respectively). ICS 205-930, a proposed 5-HT4 antagonist, competitively antagonized this response for ML-1035 (Kb = 1.6 microM) whereas atropine blocked the twitch response and any additional responses to ML-1035. In vivo, ML-1035 and metoclopramide increased gastric emptying (IC50 = 0.87 and 3.09 mg/kg i.p., respectively). Thus, the benzamides activate a 5-HT4 receptor in the ileum which increases cholinergic contractions and may be one mechanism by which these agents increase gastric emptying.
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PMID:Analysis of serotonergic mechanisms underlying benzamide-induced gastroprokinesis. 194 5

Intravenously administered 5-HT and the 5-HT3 selective agonist, 2CH3-5-HT, and the 5-HT2 selective agonist, alpha-CH3-5-HT, transiently increased heart rate in conscious, instrumented dogs. 5-HT, alpha-CH3-5-HT and 2CH3-5-HT increased systolic blood pressure in conscious dogs. The increase in blood pressure produced by alpha-CH3-5-HT was blocked by the 5-HT2 selective antagonist, LY53857, supporting a role for vascular 5-HT2 receptors in the pressor response to these amines. In contrast, LY53857 did not antagonize tachycardia produced by 2CH3-5-HT. Furthermore, propranolol also did not block 2CH3-5-HT-induced tachycardia, indicating that an indirect neuronal effect to release norepinephrine cannot explain the increase in heart rate to 2CH3-5-HT. Tachycardia to 2CH3-5-HT (as well as to isoproterenol) was modestly inhibited, but never abolished by interruption of the autonomic nervous system with atropine or hexamethonium. 5-HT3 receptor antagonists, zacopride, ICS 205-930 and GR38032F, dose-dependently blocked the tachycardia and pressor response to 2CH3-5-HT. These data establish the presence of a 5-HT3 receptor mediating a direct positive chronotropic effect of 5-HT in conscious dogs, an effect that depends, only minimally, on the presence of an intact autonomic nervous system.
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PMID:5-Hydroxytryptamine3 receptors mediate tachycardia in conscious instrumented dogs. 196 74

The racemate and (+)- and (-)-isomers of fenfluramine (5 mg kg-1 i.p., 1 h pretreatment) antagonized cisplatin-induced retching and vomiting in the ferret. The intravenous injection of (+/-)-fenfluramine administered on an established cisplatin-induced emesis antagonized the response within minutes of injection. The administration of a lower dose of (+/-)-fenfluramine (1.0 mg kg-1 i.p., 1 h pretreatment) failed to antagonize cisplatin-induced emesis when administered alone but enhanced the antiemetic effects of metoclopramide and ICS 205-930. This pretreatment with (+/-)-fenfluramine failed to enhance the antiemetic effects of zacopride. It is considered that an action of the racemate on presynaptic 5-HT/catecholaminergic systems to reduce neurotransmitter release may enhance the action of certain 5-HT3 receptor antagonists in controlling emesis induced by cisplatin.
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PMID:The actions of fenfluramine and interaction with 5-HT3 receptor-antagonists to inhibit emesis in the ferret. 197 9

The intravenous injection of cisplatin (10 mg/kg), the subcutaneous injection of apomorphine (0.125-1 mg/kg) and lisuride (0.001-0.1 mg/kg), the oral administration of ipecacuanha (0.3-2.4 mg/kg) and the intragastric administration of copper sulphate (25-100 mg/kg), induced a vomiting and retching response in the ferret. Pretreatment with dl-fenfluramine (5 mg/kg i.p.) prevented or reduced the emesis induced by cisplatin, apomorphine, ipecacuanha and lisuride but failed to significantly antagonise copper sulphate-induced emesis. The 5-HT3 receptor antagonist ICS 205-930 (0.1 mg/kg i.p.) prevented emesis induced by cisplatin and ipecacuanha but failed to prevent or significantly reduce the emesis induced by apomorphine, lisuride or copper sulphate. Dopamine receptor antagonists, including fluphenazine (0.1-1.0 mg/kg i.p.) prevented apomorphine- and lisuride-induced emesis but were less potent or had inconsistent actions to antagonise cisplatin- or ipecacuanha-induced emesis and failed to inhibit the emesis induced by copper sulphate. The data indicate that dopamine and/or 5-HT3 receptor systems are involved in drug-induced emesis but that emesis caused by gastric irritation induced by copper sulphate is mediated by different receptor mechanisms.
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PMID:Fluphenazine, ICS 205-930 and dl-fenfluramine differentially antagonise drug-induced emesis in the ferret. 197 49

Clozapine, an atypical neuroleptic drug devoid of extrapyramidal side effects, was a moderately potent, competitive inhibitor of the binding of [3H]quaternised ICS 205-930 to 5-HT3 receptor sites in rat cortical membranes, possessing a pKi value of 7.0. In contrast, several other antipsychotic agents, including fluphenazine, alpha-flupenthixol, haloperidol, spiperone and (-)-sulpiride were essentially inactive. Clozapine also antagonised the 2-methyl 5-HT-induced depolarisation of the rat isolated superior cervical ganglion, a response known to be mediated via 5-HT3 receptors. Clozapine (0.1-1 microM) induced parallel displacements to the right of the dose-response curve to 2-methyl 5-HT in this tissue, possessing a pKb value of 7.3. These data suggest that the atypical antipsychotic profile of clozapine may be related, at least, in part to its ability to interact with central 5-HT3 receptor sites.
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PMID:Interaction of the atypical neuroleptic clozapine with 5-HT3 receptors in the cerebral cortex and superior cervical ganglion of the rat. 197 90

Two subtypes of excitatory 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, are found on type 2-AH neurons of the guinea pig myenteric plexus. The 5-HT1P receptor mediates a slow and the 5-HT3 receptor a fast depolarization of these cells, however, the role of these receptors in the physiology of the gut is unknown. Renzapride (BRL 24924), a substituted benzamide, has previously been found to antagonize responses of myenteric neurons mediated by both 5-HT1P and 5-HT3 receptors. The effects on myenteric type 2-AH neurons of a structurally similar benzamide, zacopride, which unlike renzapride has S and R stereoisomers, were investigated to gain further insight into 5-HT receptor function. In contrast to renzapride, S-, but not R-zacopride, was found to mimic the 5-HT1P receptor-mediated slow response to 5-HT. Desensitization of 5-HT1P receptors with 5-HT inhibited slow depolarizing responses to S-zacopride, and desensitization with S-zacopride antagonized slow responses to 5-HT. Responses to S-zacopride were also inhibited by renzapride and the 5-HT1P receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP). S-zacopride, like renzapride and 5-HT, presynaptically inhibited nicotinic fast excitatory postsynaptic potentials, an effect that can be mediated by 5-HT1P or 5-HT1A receptors. Both S and R stereoisomers of zacopride antagonized 5-HT3 receptor-mediated fast responses to 5-HT. Unlike 5-HTP-DP, neither zacopride or its stereoisomers nor renzapride inhibited the binding of 5-[3H]HT to 5-HT1P receptors. [3H]zacopride (5-10 nM) was found to bind to a site in the gut from which it could be displaced by a 1,000-fold excess of renzapride and S-zacopride (but not R-zacopride) greater than 5-HTP-DP much greater than the 5-HT3 receptor antagonist ICS 205-930. These observations suggest that, in addition to 5-HT3 receptors, there is a benzamide binding site on myenteric neurons that interacts with, but is distinct from, the 5-HT recognition site of 5-HT1P receptors. Benzamides may affect coupling of the 5-HT1P receptor to its effector.
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PMID:Use of stereoisomers of zacopride to analyze actions of 5-hydroxytryptamine on enteric neurons. 198 11


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