Probing the Contribution of I Ks to Canine Ventricular Repolarization: Key Role for β-Adrenergic Receptor Stimulation

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-06, Vol.107 (21), p.2753-2760
• Main Authors: Volders, Paul G.A., Stengl, Milan, van Opstal, Jurren M., Gerlach, Uwe, Spätjens, Roel L.H.M.G., Beekman, Jet D.M., Sipido, Karin R., Vos, Marc A.
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000068344.54010.B3

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 APD 95 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 β-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.