Probing the contribution of I-Ks to canine ventricular repolarization - Key role for beta-adrenergic receptor stimulation

PGA Volders*, M Stengl, JM van Opstal, U Gerlach, RLHMG Spatjens, Jet D. M. Beekman, K.R. Sipido, MA Vos

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

190 Citations (Web of Science)

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 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 beta-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.
Original languageEnglish
Pages (from-to)2753-2760
JournalCirculation
Volume107
Issue number21
DOIs
Publication statusPublished - 3 Jun 2003

Keywords

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

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