TY - JOUR
T1 - Physiological consequences of transient outward K(+) current activation during heart failure in the canine left ventricle
AU - Cordeiro, Jonathan M
AU - Callø, Kirstine
AU - Moise, N Sydney
AU - Kornreich, Bruce
AU - Giannandrea, Dana
AU - Di Diego, José M
AU - Olesen, Søren-Peter
AU - Antzelevitch, Charles
N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.
PY - 2012/6
Y1 - 2012/6
N2 - 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 5weeks, +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 5weeks 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.
AB - 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 5weeks, +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 5weeks 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.
U2 - 10.1016/j.yjmcc.2012.03.001
DO - 10.1016/j.yjmcc.2012.03.001
M3 - Journal article
C2 - 22434032
SN - 0022-2828
VL - 52
SP - 1291
EP - 1298
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -