Heterogeneous distribution of the two components of delayed rectifier K+ current:: a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents

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 mu M 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 mu M) 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. (C) 1999 Elsevier Science B.V. All rights reserved.