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.