| Blockade of 5-HT-mediated enteric slow EPSPs by BRL 24924: gastrokinetic effects. | |
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MedLine Citation:
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PMID: 2782410 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Two types of 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, have been identified physiologically on enteric neurons impaled by intracellular microelectrodes. Activation of 5-HT1P receptors evokes a long-lasting membrane depolarization associated with an increased input resistance, whereas stimulation of 5-HT3 receptors results in a brief depolarization during which the input resistance falls. Slow excitatory postsynaptic potentials (EPSPs) in myenteric type II-hyperpolarizing afterpotential (AH) neurons have been demonstrated to be mediated by 5-HT1P receptors. The current experiments were done to determine whether the substituted benzamide, BRL 24924, is a specific antagonist at 5-HT1P receptors and can be used as a probe to investigate the role played by serotoninergic neurons in the control of gastrointestinal motility. Intracellular microelectrodes were used to analyze the effects of BRL 24924 on guinea pig myenteric neurons. Microejection of BRL 24924 mimicked neither the long-lasting nor the brief response to 5-HT; however, BRL 24924 (0.5-1.0 microM) reversibly antagonized both the long-lasting 5-HT1P receptor-mediated responses of myenteric neurons to 5-HT and 5-HT-mediated slow EPSPs. A greater than 10-fold higher concentration of BRL 24924 was required to reduce the short-lived responses mediated by 5-HT3 receptors. BRL 24924 did not affect the response of myenteric neurons to substance P. These results indicate that BRL 24924 is primarily a 5-HT1P antagonist. Unlike other 5-HT1P agonists or antagonists, BRL 24924 did not block the binding of 5-[3H]HT to 5-HT1P receptors. This observation suggests that specific antagonism of physiological responses to 5-HT by BRL 24924 may be the result of an action on the coupling of the 5-HT1P receptor to its effector mechanism. BRL 24924 (0.5-1 mg/kg) and another 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5 mg/kg), significantly increased the rate of emptying of a 51Cr-labeled liquid meal from the murine stomach. In contrast, the 5-HT3 antagonist, ICS 205-930 (0.1-0.5 mg/kg), did not affect the rate of gastric emptying. These observations are consistent with the hypothesis that intrinsic inhibitory neurons of the murine stomach are activated by serotoninergic axons acting through 5-HT1P receptors. Antagonism of an excitatory drive to neurons in a relaxant pathway may thus explain the gastrokinetic effects of BRL 24924. |
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Authors:
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G M Mawe; T A Branchek; M D Gershon |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The American journal of physiology Volume: 257 ISSN: 0002-9513 ISO Abbreviation: Am. J. Physiol. Publication Date: 1989 Sep |
Date Detail:
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Created Date: 1989-10-18 Completed Date: 1989-10-18 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0370511 Medline TA: Am J Physiol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: G386-96 Citation Subset: IM |
Affiliation:
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Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzamides / pharmacology* Bicyclo Compounds / pharmacology* Bicyclo Compounds, Heterocyclic* Bridged Compounds / pharmacology* Digestive System Physiological Phenomena* Electrophysiology Guinea Pigs Membrane Potentials / drug effects Microelectrodes Myenteric Plexus / drug effects*, physiology Neurons / drug effects, metabolism, physiology Receptors, Serotonin / metabolism Serotonin / metabolism, physiology* Serotonin Antagonists* Stimulation, Chemical |
| Grant Support | |
ID/Acronym/Agency:
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NS-07062/NS/NINDS NIH HHS; NS-12969/NS/NINDS NIH HHS; NS-22637/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/Bicyclo Compounds; 0/Bicyclo Compounds, Heterocyclic; 0/Bridged Compounds; 0/Receptors, Serotonin; 0/Serotonin Antagonists; 109872-41-5/renzapride; 50-67-9/Serotonin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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