title: K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization.
abstract: K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the alpha1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 microg/kg/min) in rabbits (n=74). Administration of K201 (0, 40, 100, 200 and 400 microg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 microg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 microg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 microg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an alpha1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without alpha1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.
authors.affiliation: Department of Cardiology and Pneumology, Dokkyo Medical University School of Medicine 880 Kitakobayashi, Mibu, Tochigi, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.forename: Ryuko
authors.initials: R
authors.lastname: Matsuda
authors.forename: Ken
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Hata
authors.forename: Noboru
authors.initials: N
authors.lastname: Kaneko
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; D026941:Sodium Channel Blockers; D013841:Thiazepines; C109183:K201 compound; C022799:clofilium; D008729:Methoxamine