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...
| Autores: | , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2011 |
| País: | Argentina |
| Recursos: | Universidad Nacional de La Plata |
| Repositório: | SEDICI (UNLP) |
| Idioma: | inglês |
| OAI Identifier: | oai:sedici.unlp.edu.ar:10915/84091 |
| Acesso em linha: | http://sedici.unlp.edu.ar/handle/10915/84091 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Ciencias Médicas Arrhythmias CaMKII Cardiotonic steroids Heart failure |
| Resumo: | 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. |
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