Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.

Autores
Gonano, Luis Alberto; Sepúlveda, Marisa Noemí; Morell, Malena; Toteff, Tamara; Racioppi, María Florencia; Lascano, Elena Catalina; Negroni, Jorge Antonio; Fernández Ruocco, Maria Julieta; Medei, Emiliano; Neiman, Gabriel; Miriuka, Santiago Gabriel; Back, Thomas G.; Chen, S. R. Wayne; Mattiazzi, Alicia Ramona; Vila Petroff, Martín Gerardo
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes. Conclusions Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.
Centro de Investigaciones Cardiovasculares
Consejo Nacional de Investigaciones Científicas y Técnicas
Materia
Ciencias Médicas
Apoptosis
Arrhythmias
Carvedilol
Digitalis
VK-II-86
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/124179
Acceder
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oai_identifier_str oai:sedici.unlp.edu.ar:10915/124179
network_acronym_str SEDICI
repository_id_str 1329
network_name_str SEDICI (UNLP)
spelling Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.Gonano, Luis AlbertoSepúlveda, Marisa NoemíMorell, MalenaToteff, TamaraRacioppi, María FlorenciaLascano, Elena CatalinaNegroni, Jorge AntonioFernández Ruocco, Maria JulietaMedei, EmilianoNeiman, GabrielMiriuka, Santiago GabrielBack, Thomas G.Chen, S. R. WayneMattiazzi, Alicia RamonaVila Petroff, Martín GerardoCiencias MédicasApoptosisArrhythmiasCarvedilolDigitalisVK-II-86Background It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes. Conclusions Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.Centro de Investigaciones CardiovascularesConsejo Nacional de Investigaciones Científicas y Técnicas2018-10-23info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf41-51http://sedici.unlp.edu.ar/handle/10915/124179enginfo:eu-repo/semantics/altIdentifier/issn/1347-4820info:eu-repo/semantics/altIdentifier/issn/1346-9843info:eu-repo/semantics/altIdentifier/pmid/30369562info:eu-repo/semantics/altIdentifier/doi/10.1253/circj.cj-18-0247info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-10-15T11:21:23Zoai:sedici.unlp.edu.ar:10915/124179Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-10-15 11:21:23.337SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
title Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
spellingShingle Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
Gonano, Luis Alberto
Ciencias Médicas
Apoptosis
Arrhythmias
Carvedilol
Digitalis
VK-II-86
title_short Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
title_full Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
title_fullStr Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
title_full_unstemmed Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
title_sort Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity.
dc.creator.none.fl_str_mv Gonano, Luis Alberto
Sepúlveda, Marisa Noemí
Morell, Malena
Toteff, Tamara
Racioppi, María Florencia
Lascano, Elena Catalina
Negroni, Jorge Antonio
Fernández Ruocco, Maria Julieta
Medei, Emiliano
Neiman, Gabriel
Miriuka, Santiago Gabriel
Back, Thomas G.
Chen, S. R. Wayne
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
author Gonano, Luis Alberto
author_facet Gonano, Luis Alberto
Sepúlveda, Marisa Noemí
Morell, Malena
Toteff, Tamara
Racioppi, María Florencia
Lascano, Elena Catalina
Negroni, Jorge Antonio
Fernández Ruocco, Maria Julieta
Medei, Emiliano
Neiman, Gabriel
Miriuka, Santiago Gabriel
Back, Thomas G.
Chen, S. R. Wayne
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
author_role author
author2 Sepúlveda, Marisa Noemí
Morell, Malena
Toteff, Tamara
Racioppi, María Florencia
Lascano, Elena Catalina
Negroni, Jorge Antonio
Fernández Ruocco, Maria Julieta
Medei, Emiliano
Neiman, Gabriel
Miriuka, Santiago Gabriel
Back, Thomas G.
Chen, S. R. Wayne
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
Apoptosis
Arrhythmias
Carvedilol
Digitalis
VK-II-86
topic Ciencias Médicas
Apoptosis
Arrhythmias
Carvedilol
Digitalis
VK-II-86
dc.description.none.fl_txt_mv Background It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes. Conclusions Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.
Centro de Investigaciones Cardiovasculares
Consejo Nacional de Investigaciones Científicas y Técnicas
description Background It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca2+ waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca2+ waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylation or SR Ca2+ load. Similar results could be replicated in human cardiomyocytes derived from stem cells and in a mathematical model of human myocytes. Conclusions Carvedilol and VK-II-86 are effective to prevent ouabain-induced apoptosis and spontaneous contractions indicative of arrhythmogenic activity without affecting inotropy and demonstrated to be effective in human models, thus emerging as a therapeutic tool for the prevention of digitalis-induced arrhythmias and cardiac toxicity.
publishDate 2018
dc.date.none.fl_str_mv 2018-10-23
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/124179
url http://sedici.unlp.edu.ar/handle/10915/124179
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/issn/1347-4820
info:eu-repo/semantics/altIdentifier/issn/1346-9843
info:eu-repo/semantics/altIdentifier/pmid/30369562
info:eu-repo/semantics/altIdentifier/doi/10.1253/circj.cj-18-0247
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
41-51
dc.source.none.fl_str_mv reponame:SEDICI (UNLP)
instname:Universidad Nacional de La Plata
instacron:UNLP
reponame_str SEDICI (UNLP)
collection SEDICI (UNLP)
instname_str Universidad Nacional de La Plata
instacron_str UNLP
institution UNLP
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
repository.mail.fl_str_mv alira@sedici.unlp.edu.ar
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