Clobutinol delays ventricular repolarization in the guinea pig heart: comparison with cardiac effects of HERG K+ channel inhibitor E-4031.
Clobutinol has been clinically reported to induce long QT syndrome. To clarify its cardiac electrophysiological properties, we compared effects of clobutinol on the isolated myocardium and anesthetized guinea pig heart with those of a hERG K channel blocker, E-4031. In isolated guinea pig ventricular tissues, clobutinol (3 microM) as well as E-4031 (10-100 nM) prolonged the action potential duration without affecting maximum upstroke velocity, but no further prolongation was observed after application of 30 microM clobutinol. In anesthetized closed-chest guinea pigs, clobutinol (1 and 10 mg/kg, intravenously) and E-4031 (0.01 and 1 mg/kg, intravenously) prolonged the QT interval and duration of the monophasic action potential (MAP) in a dose-dependent manner and at the same time increased the beat-to-beat variability of the MAP duration and reversed use-dependent prolongation of the MAP duration and triangulation of the MAP configuration. These results suggest that clobutinol delayed the ventricular repolarization and increased the proarrhythmic parameters linked to the hERG K channel inhibitor-induced torsade de pointes arrhythmias.
Takahara
Akira
A
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Funabashi, Chiba, Japan. akirat@phar.toho-u.ac.jp
Sasaki
Rieko
R
Nakamura
Mariko
M
Sendo
Akiko
A
Sakurai
Yukiko
Y
Namekata
Iyuki
I
Tanaka
Hikaru
H
D000200:Action Potentials / Q000187:drug effects; D000605:Amino Alcohols / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006168:Guinea Pigs; D006221:Halothane / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D016276:Ventricular Function / Q000187:drug effects* / Q000502:physiology; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
D000605:Amino Alcohols; D000996:Antitussive Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; C017135:clobutinol; D006221:Halothane