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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Scheruebel, S; Koyani, CN; Hallström, S; Lang, P; Platzer, D; Mächler, H; Lohner, K; Malle, E; Zorn-Pauly, K; Pelzmann, B.
I(f) blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes.
J Mol Cell Cardiol. 2014; 72:64-73
Doi: 10.1016/j.yjmcc.2014.02.010
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- Führende Autor*innen der Med Uni Graz
- Pelzmann Brigitte
- Scherübel-Posch Susanne
- Zorn-Pauly Klaus
- Co-Autor*innen der Med Uni Graz
- Hallström Seth
- Koyani Chintan Navinchandra
- Lang Petra
- Mächler Heinrich
- Malle Ernst
- Platzer Dieter
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- 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. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Action Potentials - drug effects
- Benzazepines - pharmacology
- Clinical Trials as Topic -
- Heart Atria - cytology Heart Atria - drug effects Heart Atria - metabolism
- Heart Rate - drug effects
- Humans -
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - antagonists & inhibitors Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism
- Lipopolysaccharides - pharmacology
- Models, Biological -
- Muscle Proteins - antagonists & inhibitors Muscle Proteins - metabolism
- Myocytes, Cardiac - cytology Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism
- Patch-Clamp Techniques -
- Potassium Channels - metabolism
- Primary Cell Culture -
- Sinoatrial Node - cytology Sinoatrial Node - drug effects Sinoatrial Node - metabolism
- Find related publications in this database (Keywords)
- Human pacemaker current
- HCN channel
- Ivabradine
- Lipopolysaccharide
- Patch clamp
- Sinoatrial cell model