I(f) blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes.
J Mol Cell Cardiol
; 72: 64-73, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24583250
ABSTRACT
Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS-HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Nó Sinoatrial
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Benzazepinas
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Potenciais de Ação
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Lipopolissacarídeos
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Miócitos Cardíacos
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Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização
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Proteínas Musculares
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article