Late Sodium Current is a New Therapeutic Target to Improve Contractility and Rhythm in Failing Heart

Author(s): Albertas Undrovinas, Victor A. Maltsev

Journal Name: Cardiovascular & Hematological Agents in Medicinal Chemistry
Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents

Volume 6 , Issue 4 , 2008

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Abstract:

Most cardiac Na+ channels open transiently within milliseconds upon membrane depolarization and are responsible for the excitation propagation. However, some channels remain active during hundreds of milliseconds, carrying the so-called persistent or late Na+ current (INaL) throughout the action potential plateau. INaL is produced by special gating modes of the cardiac-specific Na+ channel isoform. Experimental data accumulated over the past decade show the emerging importance of this late current component for the function of both normal and especially failing myocardium, where INaL is reportedly increased. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming α subunit but also by its auxiliary β subunits, cytoskeleton, and by Ca2+ signaling and trafficking proteins. Remodeling of this protein complex and intracellular signaling pathways may lead to alterations of INaL in pathological conditions. Increased INaL and the corresponding Na+ influx in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct INaL rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. New therapeutic strategies to target both arrhythmias and deficient contractility in HF may not be limited to the selective inhibition of INaL but also include multiple indirect, modulatory (e.g. Ca2+- or cytoskeleton- dependent) mechanisms of INaL function.

Keywords: Late sodium current, heart failure, calcium, action potential, numerical model, sodium-calcium exchanger

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Article Details

VOLUME: 6
ISSUE: 4
Year: 2008
Page: [348 - 359]
Pages: 12
DOI: 10.2174/187152508785909447
Price: $65

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