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Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine

Ranolazine is clinically approved for treatment of angina pectoris and is a potential candidate for antiarrhythmic, antiepileptic, and analgesic applications. These therapeutic effects of ranolazine hinge on its ability to inhibit persistent or late Na(+) currents in a variety of voltage-gated sodiu...

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Autores principales: Sokolov, S., Peters, C. H., Rajamani, S., Ruben, P. C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689222/
https://www.ncbi.nlm.nih.gov/pubmed/23801963
http://dx.doi.org/10.3389/fphar.2013.00078
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author Sokolov, S.
Peters, C. H.
Rajamani, S.
Ruben, P. C.
author_facet Sokolov, S.
Peters, C. H.
Rajamani, S.
Ruben, P. C.
author_sort Sokolov, S.
collection PubMed
description Ranolazine is clinically approved for treatment of angina pectoris and is a potential candidate for antiarrhythmic, antiepileptic, and analgesic applications. These therapeutic effects of ranolazine hinge on its ability to inhibit persistent or late Na(+) currents in a variety of voltage-gated sodium channels. Extracellular acidosis, typical of ischemic events, may alter the efficiency of drug/channel interactions. In this study, we examined pH modulation of ranolazine's interaction with the cardiac sodium channel, Na(v)1.5. We performed whole-cell path clamp experiments at extracellular pH 7.4 and 6.0 on Na(v)1.5 transiently expressed in HEK293 cell line. Consistent with previous studies, we found that ranolazine induced a stable conformational state in the cardiac sodium channel with onset/recovery kinetics and voltage-dependence resembling intrinsic slow inactivation. This interaction diminished the availability of the channels in a voltage- and use-dependent manner. Low extracellular pH impaired inactivation states leading to an increase in late Na(+) currents. Ranolazine interaction with the channel was also slowed 4–5 fold. However, ranolazine restored the voltage-dependent steady-state availability profile, thereby reducing window/persistent currents at pH 6.0 in a manner comparable to pH 7.4. These results suggest that ranolazine is effective at therapeutically relevant concentrations (10 μM), in acidic extracellular pH, where it compensates for impaired native slow inactivation.
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spelling pubmed-36892222013-06-25 Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine Sokolov, S. Peters, C. H. Rajamani, S. Ruben, P. C. Front Pharmacol Pharmacology Ranolazine is clinically approved for treatment of angina pectoris and is a potential candidate for antiarrhythmic, antiepileptic, and analgesic applications. These therapeutic effects of ranolazine hinge on its ability to inhibit persistent or late Na(+) currents in a variety of voltage-gated sodium channels. Extracellular acidosis, typical of ischemic events, may alter the efficiency of drug/channel interactions. In this study, we examined pH modulation of ranolazine's interaction with the cardiac sodium channel, Na(v)1.5. We performed whole-cell path clamp experiments at extracellular pH 7.4 and 6.0 on Na(v)1.5 transiently expressed in HEK293 cell line. Consistent with previous studies, we found that ranolazine induced a stable conformational state in the cardiac sodium channel with onset/recovery kinetics and voltage-dependence resembling intrinsic slow inactivation. This interaction diminished the availability of the channels in a voltage- and use-dependent manner. Low extracellular pH impaired inactivation states leading to an increase in late Na(+) currents. Ranolazine interaction with the channel was also slowed 4–5 fold. However, ranolazine restored the voltage-dependent steady-state availability profile, thereby reducing window/persistent currents at pH 6.0 in a manner comparable to pH 7.4. These results suggest that ranolazine is effective at therapeutically relevant concentrations (10 μM), in acidic extracellular pH, where it compensates for impaired native slow inactivation. Frontiers Media S.A. 2013-06-21 /pmc/articles/PMC3689222/ /pubmed/23801963 http://dx.doi.org/10.3389/fphar.2013.00078 Text en Copyright © 2013 Sokolov, Peters, Rajamani and Ruben. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Pharmacology
Sokolov, S.
Peters, C. H.
Rajamani, S.
Ruben, P. C.
Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title_full Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title_fullStr Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title_full_unstemmed Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title_short Proton-dependent inhibition of the cardiac sodium channel Na(v)1.5 by ranolazine
title_sort proton-dependent inhibition of the cardiac sodium channel na(v)1.5 by ranolazine
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689222/
https://www.ncbi.nlm.nih.gov/pubmed/23801963
http://dx.doi.org/10.3389/fphar.2013.00078
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