Increased late sodium current contributes to the electrophysiological effects of chronic, but not acute, dofetilide administration

Xiaoliang S. Qiu, Samuel Chauveau, Evgeny P. Anyukhovsky, Tania Rahim, Ya Ping Jiang, Erin Harleton, Steven J. Feinmark, Richard Z. Lin, Ruben Coronel, Michiel J. Janse, Tobias Opthof, Tove S. Rosen, Ira S. Cohen*, Michael R. Rosen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Background - Drugs are screened for delayed rectifier potassium current (I Kr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some I Kr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (I Na-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking I Kr and increasing I Na-L. Methods and Results - We continuously infused dofetilide (6-9 μg/kg bolus+6-9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. I Na-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an I Kr blocker with no effects on phosphoinositide 3-kinase and I Na-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. Conclusions - Increased I Na-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and I Na-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.

Original languageEnglish
Article numbere003655
JournalCirculation. Arrhythmia and Electrophysiology
Volume9
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016

Keywords

  • dofetilide
  • dogs
  • lidocaine
  • long QT syndrome
  • PI3-kinase

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