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

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 +/- 1.9 pA/pF vs 16.1 +/- 1.4 after 2 weeks and 10.7 +/- 1.4 pA/pF after 5 weeks, + 50 mV). 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 +50 mV) from 16.1 +/- 1.4 to 23.9 +/- 2.1 pA/pF (p<0.05) at 2 weeks and from 10.7 +/- 1.4 to 14.4 +/- 1.9 pA/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. (C) 2012 Elsevier Ltd. All rights reserved.