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Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study

The interaction of antiarrhythmic drugs with ion channels is often described within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is closed, open, or inacti...

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Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 1994
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2216854/
https://www.ncbi.nlm.nih.gov/pubmed/8169596
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description The interaction of antiarrhythmic drugs with ion channels is often described within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is closed, open, or inactivated. Lack of direct evidence for altered gating of cardiac Na channels allowed for the suggestion of an alternative model for drug interaction with cardiac channels, which postulated a fixed affinity receptor with access limited by the conformation of the channel (guarded receptor hypothesis). We report measurement of the gating currents of Na channels in canine cardiac Purkinje cells in the absence and presence of QX-222, a quaternary derivative of lidocaine, applied intracellularly, and benzocaine, a neutral local anesthetic. These data demonstrate that the cardiac Na channel behaves as a modulated rather than a guarded receptor in that drug-bound channels gate with altered kinetics. In addition, the results suggest a new interpretation of the modulated receptor hypothesis whereby drug occupancy reduces the overall voltage- dependence of gating, preventing full movement of the voltage sensor.
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spelling pubmed-22168542008-04-23 Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study J Gen Physiol Articles The interaction of antiarrhythmic drugs with ion channels is often described within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is closed, open, or inactivated. Lack of direct evidence for altered gating of cardiac Na channels allowed for the suggestion of an alternative model for drug interaction with cardiac channels, which postulated a fixed affinity receptor with access limited by the conformation of the channel (guarded receptor hypothesis). We report measurement of the gating currents of Na channels in canine cardiac Purkinje cells in the absence and presence of QX-222, a quaternary derivative of lidocaine, applied intracellularly, and benzocaine, a neutral local anesthetic. These data demonstrate that the cardiac Na channel behaves as a modulated rather than a guarded receptor in that drug-bound channels gate with altered kinetics. In addition, the results suggest a new interpretation of the modulated receptor hypothesis whereby drug occupancy reduces the overall voltage- dependence of gating, preventing full movement of the voltage sensor. The Rockefeller University Press 1994-01-01 /pmc/articles/PMC2216854/ /pubmed/8169596 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Articles
Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title_full Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title_fullStr Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title_full_unstemmed Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title_short Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
title_sort kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2216854/
https://www.ncbi.nlm.nih.gov/pubmed/8169596