title: Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: N Sydney
authors.initials: NS
authors.lastname: Moise
authors.forename: Bruce
authors.initials: B
authors.lastname: Kornreich
authors.forename: Dana
authors.initials: D
authors.lastname: Giannandrea
authors.forename: José M
authors.initials: JM
authors.lastname: Di Diego
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D006439:Hemodynamics; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C541204:1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea; D010671:Phenylurea Compounds; D015221:Potassium Channels; D013777:Tetrazoles; D011188:Potassium