Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias

Background-Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na +/Ca 2+ exchanger, leading to enhanced sarcoplasmic reticulum (SR) CaCa 2+ load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca 2+ i...

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Detalles Bibliográficos
Autores principales: Gonano, Luis Alberto, Sepúlveda, Marisa Noemí, Rico, Yanina, Kaetzel, Marcia, Valverde, Carlos Alfredo, Dedman, John, Mattiazzi, Alicia Ramona, Vila Petroff, Martín Gerardo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2011
Materias:
Ciencias Médicas
Arrhythmias
CaMKII
Cardiotonic steroids
Heart failure
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/84091
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-84091
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
Arrhythmias
CaMKII
Cardiotonic steroids
Heart failure
spellingShingle Ciencias Médicas
Arrhythmias
CaMKII
Cardiotonic steroids
Heart failure
Gonano, Luis Alberto
Sepúlveda, Marisa Noemí
Rico, Yanina
Kaetzel, Marcia
Valverde, Carlos Alfredo
Dedman, John
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
topic_facet Ciencias Médicas
Arrhythmias
CaMKII
Cardiotonic steroids
Heart failure
description Background-Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na +/Ca 2+ exchanger, leading to enhanced sarcoplasmic reticulum (SR) CaCa 2+ load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca 2+ i could also activate calcium-calmodulin kinase II (CaMKII), which has been shown to have proarrhythmic effects. Here, we investigate whether CaMKII underlies digitalis-induced arrhythmias and the subcellular mechanisms involved. Methods and Results-In paced rat ventricular myocytes (0.5 Hz), 50 μmol/L ouabain increased contraction amplitude by 160±5%. In the absence of electric stimulation, ouabain promoted spontaneous contractile activity and Ca 2+ waves. Ouabain activated CaMKII (p-CaMKII), which phosphorylated its downstream targets, phospholamban (PLN) (Thr17) and ryanodine receptor (RyR) (Ser2814). Ouabain-induced spontaneous activity was prevented by inhibiting CaMKII with 2.5 μmol/L KN93 but not by 2.5 μmol/L of the inactive analog, KN92. Similar results were obtained using the CaMKII inhibitor, autocamtide-2 related inhibitory peptide (AIP) (1 to 2.5 μmol/L), and in myocytes from transgenic mice expressing SR-targeted AIP. Consistently, CaMKII overexpression exacerbated ouabain-induced spontaneous contractile activity. Ouabain was associated with an increase in SR Ca 2+ content and Ca 2+ spark frequency, indicative of enhanced SR Ca 2+ leak. KN93 suppressed the ouabain-induced increase in Ca 2+ spark frequency without affecting SR Ca 2+ content. Similar results were obtained with digoxin. In vivo, ouabain-induced arrhythmias were prevented by KN93 and absent in SR-AIP mice. Conclusions-These results show for the first time that CaMKII mediates ouabain-induced arrhythmic/toxic effects. We suggest that CaMKII-dependent phosphorylation of the RyR, resulting in Ca 2+ leak from the SR, is the underlying mechanism involved.
format Articulo
Articulo
author Gonano, Luis Alberto
Sepúlveda, Marisa Noemí
Rico, Yanina
Kaetzel, Marcia
Valverde, Carlos Alfredo
Dedman, John
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
author_facet Gonano, Luis Alberto
Sepúlveda, Marisa Noemí
Rico, Yanina
Kaetzel, Marcia
Valverde, Carlos Alfredo
Dedman, John
Mattiazzi, Alicia Ramona
Vila Petroff, Martín Gerardo
author_sort Gonano, Luis Alberto
title Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
title_short Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
title_full Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
title_fullStr Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
title_full_unstemmed Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias
title_sort calcium-calmodulin kinase ii mediates digitalis-induced arrhythmias
publishDate 2011
url http://sedici.unlp.edu.ar/handle/10915/84091
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bdutipo_str Repositorios
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