title: I(f) blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes.
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.
authors.affiliation: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Scheruebel
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Chintan N
authors.initials: CN
authors.lastname: Koyani
authors.affiliation: Institute of Physiological Chemistry, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Seth
authors.initials: S
authors.lastname: Hallström
authors.affiliation: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Lang
authors.affiliation: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Platzer
authors.affiliation: Division of Cardiac Surgery, Medical University of Graz, Auenbruggerplatz, A-8010 Graz, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Mächler
authors.affiliation: Institute of Molecular Biosciences, Biophysics Division, University of Graz, Schmiedlstrasse 6, A-8042 Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Lohner
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.affiliation: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria. Electronic address: klaus.zornpauly@medunigraz.at.
authors.forename: Klaus
authors.initials: K
authors.lastname: Zorn-Pauly
authors.affiliation: Institute of Biophysics, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria. Electronic address: brigitte.pelzmann@medunigraz.at.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pelzmann
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077550:Ivabradine; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008954:Models, Biological; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D061251:Primary Cell Culture; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001552:Benzazepines; C578710:HCN2 protein, human; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D015221:Potassium Channels; D000077550:Ivabradine
keywords: HCN channel; Human pacemaker current; Ivabradine; Lipopolysaccharide; Patch clamp; Sinoatrial cell model