title: Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs.
abstract: The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca2+ current (ICaL) caused by a decrease in Ca2+-dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.
authors.affiliation: Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.|Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Jae Gon
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Division of Sport Science, College of Science and Technology, Konkuk University, Choongju, South Korea.
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Sung
authors.affiliation: Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Hyun-ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, South Korea.
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, South Korea.
authors.forename: Kyung Jong
authors.initials: KJ
authors.lastname: Won
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, South Korea.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul, South Korea.
authors.forename: Ho Chul
authors.initials: HC
authors.lastname: Shin
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon, South Korea.|Human and Environmental Toxicology Program, University of Science and Technology, Daejeon, South Korea.
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Chae Hun
authors.initials: CH
authors.lastname: Leem
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Physiology and the Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju, South Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D024841:Fluoroquinolones / Q000494:pharmacology*; D006352:Heart Ventricles / Q000473:pathology; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D026902:Potassium Channel Blockers; C061363:sparfloxacin