I(Ks) restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation

D.M. Johnson, J. Heijman, Chris E. Pollard, J. P. Valentin, H.J. Crijns, N. Abi-Gerges, P.G.A. Volders*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I-Ks blockade versus I-Kr blockade and late-I-Na augmentation, under the influence of beta-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I-Ks was blocked by HMR1556, I-Kr by dofetilide. Late I-Na was augmented by sea anemone toxin-II. Isoproterenol was added for beta-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca2+. SEA0400 partially inhibited the Na+-Ca2+ exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Sigma(vertical bar APD90; i+1 minus APD90; i vertical bar)/[nbeats x root 2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I-Kr blockade and late-I-Na augmentation, especially at slow pacing rates. beta-adrenergic stimulation restabilized these BVR changes. In contrast, I-Ks blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during beta-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, beta-adrenergic receptor stimulation exaggerates BVR during I-Ks blockade, indicating a BVR-stabilizing role of beta-adrenergic-sensitive I-Ks. Loss of I-Ks plus overriding of Ca2+-dependent membrane currents, including inward Na+-Ca2+ exchange current, conspire to proarrhythmic BVR under these conditions.
Original languageEnglish
Pages (from-to)122-130
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number1
DOIs
Publication statusPublished - Jan 2010

Keywords

  • Action potential
  • Arrhythmia
  • Beta-adrenergic receptor stimulation
  • Calcium
  • Contraction
  • Ion channels
  • Potassium
  • Sodium-calcium exchanger
  • Repolarization
  • Ventricles

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