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(Circulation. 2005;112:1392-1399.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Restricting Excessive Cardiac Action Potential and QT Prolongation

A Vital Role for I_Ks in Human Ventricular Muscle

Norbert Jost, PhD; László Virág, PhD; Miklós Bitay, MD, PhD; János Takács, MD, PhD; Csaba Lengyel, MD, PhD; Péter Biliczki, MD; Zsolt Nagy, MSc; Gábor Bogáts, MD, PhD; David A. Lathrop, PhD; Julius G. Papp, MD, DSc; András Varró, MD, DSc

From the Department of Pharmacology and Pharmacotherapy (N.J., L.V., J.T., P.B., Z.N., J.G.P., A.V.), Department of Cardiac Surgery (M.B., G.B.), and First Department of Internal Medicine (C.L.), University of Szeged, and Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences (N.J., J.G.P.), Szeged, Hungary, and Heart Research Program (D.A.L.), National Heart, Lung and Blood Institute, Bethesda, Md.

Correspondence to Professor András Varró, Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, PO Box 427, Hungary. E-mail a.varro{at}phcol.szote.u-szeged.hu

Received March 17, 2005; revision received July 7, 2005; accepted July 11, 2005.

Background— Although pharmacological block of the slow, delayed rectifier potassium current (I_Ks) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of I_Ks block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of I_Ks in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline.

Methods and Results— Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 µmol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 µmol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I_Kr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked I_Ks in the presence of E-4031 to block I_Kr. The E-4031–sensitive current (I_Kr) at the end of a 150-ms-long test pulse to 30 mV was 32.9±6.7 pA (n=8); the L-735,821–sensitive current (I_Ks) magnitude was 17.8±2.94 pA (n=10). During a longer 500-ms test pulse, I_Kr was not substantially changed (33.6±6.1 pA; n=8), and I_Ks was significantly increased (49.6±7.24 pA; n=10). On application of an "action potential–like" test pulse, I_Kr increased as voltage became more negative, whereas I_Ks remained small throughout all phases of the action potential–like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 µmol/L adrenaline, 1 µmol/L HMR-1556 significantly increased APD by 14.7±3.2% (P<0.05; n=3).

Conclusions— Pharmacological I_Ks block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, I_Ks plays an increasingly important role in limiting action potential prolongation.

Key Words: arrhythmia • electrophysiology • ion channels • long-QT syndrome • potassium channels

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