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Suppression of vent...
Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current
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- Angelini, Marina (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Pezhouman, Arash (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Savalli, Nicoletta (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Chang, Marvin G. (author)
- Harvard Med Sch, MA 02115 USA
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- Steccanella, Federica (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Scranton, Kyle (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Calmettes, Guillaume (author)
- Univ Calif Los Angeles, CA 90095 USA
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- Ottolia, Michela (author)
- Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA
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- Pantazis, Antonios (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Karagueuzian, Hrayr S. (author)
- Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA
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- Weiss, James N. (author)
- Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA
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- Olcese, Riccardo (author)
- Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA
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(creator_code:org_t)
- 2021-10-26
- 2021
- English.
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In: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 153:12
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of I-Ca,I-L, compromising inotropy. However, computational studies have recently demonstrated that selective reduction of late I-Ca,I-L (Ca2+ influx during late phases of the action potential) is sufficient to potently suppress EADs, suggesting that effective antiarrhythmic action can be achieved without blocking the early peak I-Ca,I-L, which is essential for proper excitation-contraction coupling. We tested this new strategy using a purine analogue, roscovitine, which reduces late I-Ca,I-L with minimal effect on peak current. Scaling our investigation from a human Ca(V)1.2 channel clone to rabbit ventricular myocytes and rat and rabbit perfused hearts, we demonstrate that (1) roscovitine selectively reduces I-Ca,I-L noninactivating component in a human Ca(V)1.2 channel clone and in ventricular myocytes native current, (2) the pharmacological reduction of late I-Ca,I-L suppresses EADs and EATs (early after Ca2+ transients) induced by oxidative stress and hypokalemia in isolated myocytes, largely preserving cell shortening and normal Ca2+ transient, and (3) late I-Ca,I-L reduction prevents/suppresses ventricular tachycardia/fibrillation in ex vivo rabbit and rat hearts subjected to hypokalemia and/or oxidative stress. These results support the value of an antiarrhythmic strategy based on the selective reduction of late I-Ca,I-L to suppress EAD-mediated arrhythmias. Antiarrhythmic therapies based on this idea would modify the gating properties of Ca(V)1.2 channels rather than blocking their pore, largely preserving contractility.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Angelini, Marina
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Pezhouman, Arash
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Savalli, Nicolet ...
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Chang, Marvin G.
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Steccanella, Fed ...
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Scranton, Kyle
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Calmettes, Guill ...
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Ottolia, Michela
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Pantazis, Antoni ...
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Karagueuzian, Hr ...
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Weiss, James N.
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Olcese, Riccardo
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Physiology
- Articles in the publication
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The Journal of G ...
- By the university
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Linköping University