Abstract
Blockade of IKr prolongs action potential duration (APD) and may cause lethal arrhythmia such as torsades de pointes. The risk of this arrhythmia depends on voltage- and time-dependence of IKr blockade. In the present study, we introduced a novel method that can assess the risk of IKr blockers with variation of IKs channel density in the ventricular myocardium. In this method, the Luo-Rudy phase II model was adopted to calculate drug-induced prolongation of APD and the effects of IKr blockers (such as dofetilide, quinidine and vesnarinone) under the various magnitudes of IKs were shown in a two-dimensional contour map. For the tachycardia condition, the slope of APD-isoline in the IKr (horizontal axis)–IKs (vertical axis) map was large. This corresponds to the weak effect of the IKr blockade due to the accumulation of the IKs. The voltage- and time-dependence of IKr blockers, such as quinidine and vesnarinone, curved isolines in the map and the curvature for vesnarinone was increased under bradycardia. Because the IKr block accumulates at short cycle length due to the long time constant of the block by vesnarinone. These results suggest that the two-dimensional mapping is a useful method to estimate arrhythmogenic risk of IKr blockers. [J Physiol Sci. 2007;57 Suppl:S206]
