Heterogeneous distribution of the two components of delayed rectifier K+ current: A potential mechanism of the proarrhythmic effects of methanesulfonanilideclass III agents

Abstract

Objective: To elucidate the regional difference of the K+ current blocking effects of methanesulfonanilide class III agents. Methods: Regional differences in action potential duration (APD) and E-4031-sensitive component (I(Kr)) as well as -insensitive component (I(Ks)) of the delayed rectifier K+ current (I(K)) were investigated in enzymatically isolated myocytes from apical and basal regions of the rabbit left ventricle using the whole-cell clamp technique. Results: At 1 Hz stimulation, APD was significantly longer in the apex than in the base (223.1±10.6 vs. 182.7±14.5 ms, p<0.05); application of 1 μM E-4031 caused more significant APD prolongation in the apex than in the base (32.5±6.4% vs. 21.0±8.8%, p<0.05), resulting in an augmentation of regional dispersion of APD. In response to a 3-s depolarization pulse to +40 mV from a holding potential of -50 mV, both I(K) tail and I(Ks) tail densities were significantly smaller in apical than in basal myocytes (I(K): 1.56±0.13 vs. 2.09±0.21 pA/pF, p<0.05; I(Ks): 0.40±0.15 vs. 1.43±0.23, p<0.01), whereas I(Kr) tail density was significantly greater in the apex than in the base (1.15-±0.13 vs. 0.66±0.11 pA/pF, p<0.01). The ratio of I(Ks)/I(Kr) for the tail current in the apex was significantly smaller than that in the base (0.51±0.21 vs. 3.09±0.89; p<0.05). No statistical difference was observed in the voltage dependence as well as activation and deactivation kinetics of I(Kr) and I(Ks) between the apex and base. Isoproterenol (1 μM) increased the time-dependent outward current of I(Ks) by 111±8% during the 3-s depolarizing step at +40 mV and its tail current by 120±9% on repolarization to the holding potential of -50 mV, whereas it did not affect I(Kr). Conclusions: The regional differences in I(K), in particular differences in its two components may underlie the regional disparity in APD, and that methanesulfonanilide class III antiarrhythmic agents such as E-4031 may cause a greater spatial inhomogeneity of ventricular repolarization, leading to re-entrant arrhythmias.