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(Circulation. 2003;107:2753.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Probing the Contribution of I_Ks to Canine Ventricular Repolarization

Key Role for ß-Adrenergic Receptor Stimulation

Paul G.A. Volders, MD, PhD; Milan Stengl, MD, PhD; Jurren M. van Opstal, MD, PhD; Uwe Gerlach, PhD; Roel L.H.M.G. Spätjens, BS; Jet D.M. Beekman; Karin R. Sipido, MD, PhD; Marc A. Vos, PhD

From the Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, Netherlands; Aventis Pharma Deutschland GmbH, Medicinal Chemistry (U.G.), Frankfurt/Main, Germany; and the Laboratory of Experimental Cardiology (K.R.S.), University of Leuven, Belgium.

Correspondence to Paul G.A. Volders, MD, PhD, Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, Netherlands. E-mail p.volders{at}cardio.azm.nl

Background— In large mammals and humans, the contribution of I_Ks to ventricular repolarization is still incompletely understood.

Methods and Results— In vivo and cellular electrophysiological experiments were conducted to study I_Ks in canine ventricular repolarization. In conscious dogs, administration of the selective I_Ks blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, I_Ks block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of I_Ks in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated I_Ks activation to promote APD₉₅ shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by I_Kr block, I_Ks block exaggerated repolarization instability with further prolongation of APD.

Conclusions— Ventricular repolarization in conscious dogs is importantly dependent on I_Ks. I_Ks function becomes prominent during ß-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during I_Kr block, when it limits repolarization instability by time-dependent activation. Unstimulated I_Ks does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal I_Ks and the sympathetic nervous system in vivo.

Key Words: ion channels • action potentials • receptors, adrenergic, beta • long-QT syndrome • ventricles

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