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: Hisashi Hasumi, Ryuko Matsuda, Ken Shimamoto, Yoshihito Hata, Noboru Kaneko
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 555 Issue 1 Pg. 54-60 (Jan 19 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17112502 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-1 Receptor Agonists
• Adrenergic alpha-Agonists
• Anti-Arrhythmia Agents
• Calcium Channel Blockers
• Cardiotonic Agents
• Potassium Channel Blockers
• Quaternary Ammonium Compounds
• Sodium Channel Blockers
• Thiazepines
• K201 compound
• clofilium
• Methoxamine

Topics

• Adrenergic alpha-1 Receptor Agonists
• Adrenergic alpha-Agonists (pharmacology)
• Animals
• Anti-Arrhythmia Agents
• Blood Pressure (drug effects)
• Calcium Channel Blockers (pharmacology)
• Cardiotonic Agents (pharmacology)
• Electrocardiography
• Heart Rate (drug effects)
• Long QT Syndrome (chemically induced, physiopathology)
• Male
• Methoxamine (pharmacology)
• Potassium Channel Blockers (pharmacology)
• Quaternary Ammonium Compounds
• Rabbits
• Sodium Channel Blockers (pharmacology)
• Thiazepines (pharmacology)
• Torsades de Pointes (chemically induced, physiopathology, prevention & control)