This Article Full Text Full Text (PDF) All Versions of this Article: 112/10/1392    most recent CIRCULATIONAHA.105.550111v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jost, N. Articles by Varró, A. Search for Related Content PubMed PubMed Citation Articles by Jost, N. Articles by Varró, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Arrythmias-basic studies Related Article

(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

Related Article:

Protecting the Heart Against Arrhythmias: Potassium Current Physiology and Repolarization Reserve

Dan M. Roden and Tao Yang
Circulation 2005 112: 1376-1378. [Extract] [Full Text]

This article has been cited by other articles:

				R. J. Selvaraj, A. M. Suszko, A. Subramanian, K. Nanthakumar, and V. S. Chauhan Adrenergic stimulation increases repolarization dispersion and reduces activation-repolarization coupling along the RV endocardium of patients with cardiomyopathy Europace, November 1, 2009; 11(11): 1529 - 1535. [Abstract] [Full Text] [PDF]

				H. Itoh, T. Sakaguchi, W.-G. Ding, E. Watanabe, I. Watanabe, Y. Nishio, T. Makiyama, S. Ohno, M. Akao, Y. Higashi, et al. Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome Circ Arrhythm Electrophysiol, October 1, 2009; 2(5): 511 - 523. [Abstract] [Full Text] [PDF]

				L. Romero, E. Pueyo, M. Fink, and B. Rodriguez Impact of ionic current variability on human ventricular cellular electrophysiology Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1436 - H1445. [Abstract] [Full Text] [PDF]

				G. Piccirillo, D. Magri, M. Ogawa, J. Song, V. J. Chong, S. Han, B. Joung, E.-K. Choi, S. Hwang, L. S. Chen, et al. Autonomic Nervous System Activity Measured Directly and QT Interval Variability in Normal and Pacing-Induced Tachycardia Heart Failure Dogs. J. Am. Coll. Cardiol., August 25, 2009; 54(9): 840 - 850. [Abstract] [Full Text] [PDF]

				M. Jiang, X. Xu, Y. Wang, F. Toyoda, X.-S. Liu, M. Zhang, R. B. Robinson, and G.-N. Tseng Dynamic Partnership between KCNQ1 and KCNE1 and Influence on Cardiac IKs Current Amplitude by KCNE2 J. Biol. Chem., June 12, 2009; 284(24): 16452 - 16462. [Abstract] [Full Text] [PDF]

				S. Nattel Delayed-rectifier potassium currents and the control of cardiac repolarization: Noble and Tsien 40 years after J. Physiol., December 15, 2008; 586(24): 5849 - 5852. [Full Text] [PDF]

				A. Sridhar, Y. Nishijima, D. Terentyev, R. Terentyeva, R. Uelmen, M. Kukielka, I. M. Bonilla, G. A. Robertson, S. Gyorke, G. E. Billman, et al. Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1463 - R1472. [Abstract] [Full Text] [PDF]

				J. P. Imredy, J. R. Penniman, S. J. Dech, W. D. Irving, and J. J. Salata Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1867 - H1881. [Abstract] [Full Text] [PDF]

				Y. Rudy, M. J. Ackerman, D. M. Bers, C. E. Clancy, S. R. Houser, B. London, A. D. McCulloch, D. A. Przywara, R. L. Rasmusson, R. J. Solaro, et al. Systems Approach to Understanding Electromechanical Activity in the Human Heart: A National Heart, Lung, and Blood Institute Workshop Summary Circulation, September 9, 2008; 118(11): 1202 - 1211. [Abstract] [Full Text] [PDF]

				D. M. Roden Repolarization Reserve: A Moving Target Circulation, September 2, 2008; 118(10): 981 - 982. [Full Text] [PDF]

				L. Xiao, J. Xiao, X. Luo, H. Lin, Z. Wang, and S. Nattel Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve Circulation, September 2, 2008; 118(10): 983 - 992. [Abstract] [Full Text] [PDF]

				C. S. Nicolas, K.-H. Park, A. El Harchi, J. Camonis, R. S. Kass, D. Escande, J. Merot, G. Loussouarn, F. Le Bouffant, and I. Baro IKs response to protein kinase A-dependent KCNQ1 phosphorylation requires direct interaction with microtubules Cardiovasc Res, August 1, 2008; 79(3): 427 - 435. [Abstract] [Full Text] [PDF]

				X. Xu, M. Jiang, K.-L. Hsu, M. Zhang, and G.-N. Tseng KCNQ1 and KCNE1 in the IKs Channel Complex Make State-dependent Contacts in their Extracellular Domains J. Gen. Physiol., June 1, 2008; 131(6): 589 - 603. [Abstract] [Full Text] [PDF]

				C. Sims, S. Reisenweber, P. C. Viswanathan, B.-R. Choi, W. H. Walker, and G. Salama Sex, Age, and Regional Differences in L-Type Calcium Current Are Important Determinants of Arrhythmia Phenotype in Rabbit Hearts With Drug-Induced Long QT Type 2 Circ. Res., May 9, 2008; 102(9): e86 - e100. [Abstract] [Full Text] [PDF]

				I. R. Boulet, A. J. Labro, A. L. Raes, and D. J. Snyders Role of the S6 C-terminus in KCNQ1 channel gating J. Physiol., December 1, 2007; 585(2): 325 - 337. [Abstract] [Full Text] [PDF]

				D. J. Gallacher, A. Van de Water, H. van der Linde, A. N. Hermans, H. R. Lu, R. Towart, and P. G.A. Volders In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome Cardiovasc Res, November 1, 2007; 76(2): 247 - 256. [Abstract] [Full Text] [PDF]

				K. Ahmad and P. Dorian Drug-induced QT prolongation and proarrhythmia: an inevitable link? Europace, September 1, 2007; 9(suppl_4): iv16 - iv22. [Abstract] [Full Text] [PDF]

				G. Antoons, P. G. A. Volders, T. Stankovicova, V. Bito, M. Stengl, M. A. Vos, and K. R. Sipido Window Ca2+ current and its modulation by Ca2+ release in hypertrophied cardiac myocytes from dogs with chronic atrioventricular block J. Physiol., February 15, 2007; 579(1): 147 - 160. [Abstract] [Full Text] [PDF]

				C. Lengyel, L. Virag, T. Biro, N. Jost, J. Magyar, P. Biliczki, E. Kocsis, R. Skoumal, P. P. Nanasi, M. Toth, et al. Diabetes mellitus attenuates the repolarization reserve in mammalian heart Cardiovasc Res, February 1, 2007; 73(3): 512 - 520. [Abstract] [Full Text] [PDF]

				Z. Mustapha, L. Pang, and S. Nattel Characterization of the cardiac KCNE1 gene promoter Cardiovasc Res, January 1, 2007; 73(1): 82 - 91. [Abstract] [Full Text] [PDF]

				E. Schulze-Bahr Arrhythmia Predisposition: Between Rare Disease Paradigms and Common Ion Channel Gene Variants J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A67 - A78. [Abstract] [Full Text] [PDF]

				M. Stengl, C. Ramakers, D. W. Donker, A. Nabar, A. V. Rybin, R. L.H.M.G. Spatjens, T. van der Nagel, W. K.W.H. Wodzig, K. R. Sipido, G. Antoons, et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted {beta}-adrenergic activation Cardiovasc Res, October 1, 2006; 72(1): 90 - 100. [Abstract] [Full Text] [PDF]

				A. Varro and J. Gy. Papp Low penetrance, subclinical congenital LQTS: Concealed LQTS or silent LQTS? Cardiovasc Res, June 1, 2006; 70(3): 404 - 406. [Full Text] [PDF]

				I. R. Boulet, A. L. Raes, N. Ottschytsch, and D. J. Snyders Functional effects of a KCNQ1 mutation associated with the long QT syndrome Cardiovasc Res, June 1, 2006; 70(3): 466 - 474. [Abstract] [Full Text] [PDF]

				G. Poglajen, M. Fister, B. Radovancevic, and B. Vrtovec Short QT Interval and Atrial Fibrillation in Patients Without Structural Heart Disease J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1905 - 1907. [Full Text] [PDF]

				D. M. Roden A New Role for Calmodulin in Ion Channel Biology Circ. Res., April 28, 2006; 98(8): 979 - 981. [Full Text] [PDF]

				D. M. Roden and T. Yang Protecting the Heart Against Arrhythmias: Potassium Current Physiology and Repolarization Reserve Circulation, September 6, 2005; 112(10): 1376 - 1378. [Full Text] [PDF]