title: Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs.
abstract: An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi Ota-ku, Tokyo 143-8540, Japan. Electronic address: atsushi.sugiyama@med.toho-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D004285:Dogs; D005260:Female; D006221:Halothane; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D018685:Anesthetics, Inhalation; D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; C063968:E 4031; D006221:Halothane
keywords: E-4031; E-4031 (PubChem CID: 3087190); Electro-mechanical relationship; Halothane-anesthetized dog; I(Kr); Positive inotropic action; QT prolongation