Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells

Zhenghang Zhao, Yuanfang Xie, Hairuo Wen, Dandan Xiao, Charelle Allen, Nadezhda Fefelova, Wen Dun, Penelope A. Boyden, Zhilin Qu, Lai Hua Xie

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Aims: The transient outward potassium current (Ito) plays important roles in action potential (AP) morphology and dynamics; however, its role in the genesis of early afterdepolarizations (EADs) is not well understood. We aimed to study the effects and mechanisms of Ito on EAD genesis in cardiac cells using combined experimental and computational approaches. Methods and results: We first carried out patch-clamp experiments in isolated rabbit ventricular myocytes exposed to H2O2 (0.2 or 1 mM), in which EADs were induced at a slow pacing rate. EADs were eliminated by either increasing the pacing rate or blocking Ito with 2 mM 4-aminopyridine. In addition to enhancing the L-type calcium current (I Ca,L) and the late sodium current, H2O2 also increased the conductance, slowed inactivation, and accelerated recovery from the inactivation of Ito. Computer simulations showed that I to promoted EADs under the condition of reduced repolarization reserve, consistent with the experimental observations. However, EADs were only promoted in the intermediate ranges of the Ito conductance and the inactivation time constant. The underlying mechanism is that Ito lowers the AP plateau voltage into the range at which the time-dependent potassium current (namely IKs) activation is further slowed and ICa,L is available for reactivation, leading to voltage oscillations to manifest EADs. Further experimental studies in cardiac cells of other species validated the theoretical predictions. Conclusion: In cardiac cells, I to, with a proper conductance and inactivation speed, potentiates EADs by setting the AP plateau into the voltage range where ICa,L reactivation is facilitated and IKs activation is slowed.

Original languageEnglish (US)
Pages (from-to)308-316
Number of pages9
JournalCardiovascular research
Volume95
Issue number3
DOIs
StatePublished - 2012

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Cardiac arrhythmias
  • Computer model
  • Dynamic mechanisms
  • Early afterdepolarization
  • Transient outward current

Fingerprint

Dive into the research topics of 'Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells'. Together they form a unique fingerprint.

Cite this