title: Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4.
abstract: In Europe, ivabradine has recently been approved to treat patients with angina who have intolerance to beta blockers and/or heart failure. Ivabradine is considered to act specifically on the sinoatrial node by inhibiting the If current (the funny current) to slow automaticity. However, in vitro studies show that ivabradine prolongs phase 3 repolarization in ventricular tissue. No episodes of Torsades de Pointes have been reported in randomized clinical studies. The objective of this study is to assess whether ivabradine blocked the hERG1 current. In the present study we discovered that ivabradine prolongs action potential and blocks the hERG current over a range of concentrations overlapping with those required to block HCN4. Ivabradine produced tonic, rather than use-dependent block. The mutation Y652A significantly suppressed pharmacologic block of hERG by ivabradine. Disruption of C-type inactivation also suppressed block of hERG1 by ivabradine. Molecular docking and molecular dynamics simulations indicate that ivabradine may access the inner cavity of the hERG1 via a lipophilic route and has a well-defined binding site in the closed state of the channel. Structural organization of the binding pockets for ivabradine is discussed. Ivabradine blocks hERG and prolongs action potential duration. Our study is potentially important because it indicates the need for active post marketing surveillance of ivabradine. Importantly, proarrhythmia of a number of other drugs has only been discovered during post marketing surveillance.
authors.affiliation: Libin Cardiovascular Institute and Department of Medicine, University of Calgary, Alberta, Canada.
authors.forename: James P
authors.initials: JP
authors.lastname: Lees-Miller
authors.affiliation: Libin Cardiovascular Institute and Department of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Alberta, Canada.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Alberta, Canada.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Perissinotti
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Alberta, Canada. Electronic address: noskovsy@gmail.com.
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Noskov
authors.affiliation: Libin Cardiovascular Institute and Department of Medicine, University of Calgary, Alberta, Canada. Electronic address: hduff@ucalgary.ca.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000200:Action Potentials; D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D000077550:Ivabradine; D008051:Lipid Bilayers / Q000737:chemistry; D051379:Mice; D062105:Molecular Docking Simulation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D001552:Benzazepines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C578706:Hcn4 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C000606913:KCNH2 protein, human; C000606915:Kcnh2 protein, mouse; D008051:Lipid Bilayers; D026902:Potassium Channel Blockers; D000077550:Ivabradine
keywords: Ivabradine; Potassium channels; Tonic block; hERG KCNH2