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

Abstract

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.