Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle

J Mol Cell Cardiol. 2012 Jun;52(6):1291-8. doi: 10.1016/j.yjmcc.2012.03.001. Epub 2012 Mar 11.


Background: Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing-induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current.

Method and results: Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1±1.9pA/pF vs 16.1±1.4 after 2weeks and 10.7±1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1±1.4 to 23.9±2.1pA/pF (p<0.05) at 2weeks and from 10.7±1.4 to 14.4±1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs.

Conclusions: The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiac Output / drug effects
  • Disease Models, Animal
  • Dogs
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology*
  • Hemodynamics
  • Pericardium / drug effects
  • Pericardium / metabolism
  • Pericardium / physiopathology
  • Phenylurea Compounds / pharmacology
  • Potassium / metabolism*
  • Potassium Channels / agonists
  • Potassium Channels / metabolism*
  • Tetrazoles / pharmacology


  • 1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea
  • Phenylurea Compounds
  • Potassium Channels
  • Tetrazoles
  • Potassium