title: Repolarization reserve evolves dynamically during the cardiac action potential: effects of transient outward currents on early afterdepolarizations.
abstract: BACKGROUND
  Transient outward K currents (Ito) have been reported both to suppress and to facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here, we used the dynamic clamp technique to analyze how Ito accounts for these paradoxical effects on EADs by influencing the dynamic evolution of repolarization reserve during the action potential.
  
  
  RESULTS
  Isolated patch-clamped rabbit ventricular myocytes were exposed to either oxidative stress (H2O2) or hypokalemia to induce bradycardia-dependent EADs at a long pacing cycle length of 6 s, when native rabbit Ito is substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when Ito becomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the Ito blocker 4-aminopyridine, but reappeared when a virtual current with appropriate Ito-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s pacing cycle length in the absence of 4-aminopyridine, adding a virtual Ito-like current (n=1113 trials) caused EADs to reappear over a wide range of Ito conductance (0.005-0.15 nS/pF), particularly when inactivation kinetics were slow (τinact≥20 ms) and the pedestal (noninactivating component) was small (<25% of peak Ito). Faster inactivation or larger pedestals tended to suppress EADs.
  
  
  CONCLUSIONS
  Repolarization reserve evolves dynamically during the cardiac action potential. Whereas sufficiently large Ito can suppress EADs, a wide range of intermediate Ito properties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting Ito as an antiarrhythmic strategy.
authors.affiliation: From the UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles. tpnguyen@mednet.ucla.edu.
authors.forename: Thao P
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: From the UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: Neha
authors.initials: N
authors.lastname: Singh
authors.affiliation: From the UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: From the UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: From the UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001919:Bradycardia / Q000378:metabolism / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007008:Hypokalemia / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
chemical_list: D015221:Potassium Channels; D006861:Hydrogen Peroxide; D011188:Potassium
keywords: arrhythmias, cardiac; dynamic clamp; early afterdepolarization; repolarization reserve; transient outward potassium current