| Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. | |
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MedLine Citation:
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PMID: 11046096 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Administration of the 5-hydroxytryptamine 3 receptor class of antiemetic agents has been associated with prolongation in the QRS, JT, and QT intervals of the ECG. To explore the mechanisms underlying these findings, we examined the effects of granisetron, ondansetron, dolasetron, and the active metabolite of dolasetron MDL 74,156 on the cloned human cardiac Na(+) channel hH1 and the human cardiac K(+) channel HERG and the slow delayed rectifier K(+) channel KvLQT1/minK. Using patch-clamp electrophysiology we found that all of the drugs blocked Na(+) channels in a frequency-dependent manner. At a frequency of 3 Hz, the IC(50) values for block of Na(+) current measured 2.6, 88.5, 38.0, and 8.5 microM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Block was relieved by strong hyperpolarizing potentials, suggesting a possible interaction with an inactivated channel state. Recovery from inactivation was impaired at -80 mV compared with -100 mV, and the fractional recovery was impaired by drug in a concentration-dependent manner. IC(50) values for block of the HERG cardiac K(+) channel measured 3.73, 0.81, 5.95, and 12.1 microM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Ondansetron (3 microM) also slowed decay of HERG tail currents. In contrast, none of these drugs (10 microM) produced greater than 30% block of the slow delayed rectifier K(+) channel KvLQT1/minK. We concluded that the antiemetic agents tested in this study block human cardiac Na(+) channels probably by interacting with the inactivated state. This may lead to clinically relevant Na(+) channel blockade, especially when high heart rates or depolarized/ischemic tissue is present. The submicromolar affinity of ondansetron for the HERG K(+) channel likely underlies the prolongation of cardiac repolarization reported for this drug. |
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Authors:
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Y A Kuryshev; A M Brown; L Wang; C R Benedict; D Rampe |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 295 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2000 Nov |
Date Detail:
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Created Date: 2000-11-02 Completed Date: 2000-11-21 Revised Date: 2008-10-28 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 614-20 Citation Subset: IM |
Affiliation:
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ChanTest, Inc., Cleveland, Ohio, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antiemetics
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pharmacology* Cation Transport Proteins* Cell Line Cloning, Molecular DNA-Binding Proteins* Dose-Response Relationship, Drug Electric Stimulation Ether-A-Go-Go Potassium Channels Granisetron / pharmacology Heart / drug effects*, physiology Humans Indoles / pharmacology KCNQ Potassium Channels KCNQ1 Potassium Channel Ondansetron / pharmacology Potassium Channels / drug effects, genetics, physiology* Potassium Channels, Voltage-Gated* Quinolizines / pharmacology Receptors, Serotonin / drug effects, physiology* Receptors, Serotonin, 5-HT3 Serotonin Antagonists / pharmacology* Sodium Channels / drug effects, genetics, physiology* Trans-Activators* Transfection |
| Chemical | |
Reg. No./Substance:
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0/Antiemetics; 0/Cation Transport Proteins; 0/DNA-Binding Proteins; 0/ERG protein, human; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/Indoles; 0/KCNH6 protein, human; 0/KCNQ Potassium Channels; 0/KCNQ1 Potassium Channel; 0/KCNQ1 protein, human; 0/Potassium Channels; 0/Potassium Channels, Voltage-Gated; 0/Quinolizines; 0/Receptors, Serotonin; 0/Receptors, Serotonin, 5-HT3; 0/Serotonin Antagonists; 0/Sodium Channels; 0/Trans-Activators; 109889-09-0/Granisetron; 115956-13-3/dolasetron mesylate; 99614-02-5/Ondansetron |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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