Physiological Effects of Transient Outward K+ Current Activation during Heart Failure in the Canine Left Ventricle

Abstract

Introduction: Remodeling of ion channel expression is well established in heart failure (HF). Loss of transient outward current (Ito) during HF contributes to repolarization abnormalities. We determined the extent to which Ito is reduced in tachypacing-induced HF and assessed the ability of an Ito activator (NS5806) to recover this current. Methods: Whole cell patch clamp was used to record Ito in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular (LV) wedge preparations. Results: Rapid pacing resulted in a reduction in the size of Ito in Epi myocytes (Control= 22.13±1.9 pA/pF vs 16.12±1.4 after 2-weeks and 10.69±1.4 pA/pF after 5-weeks, +50 mV). HF also slowed the recovery of Ito. Recovery of Ito showed a fast and slow phase as follows: i) 1=28.4±2.54 ms and 2= 177.5±7.82 ms for Control Epi, ii) 1=56.6±5.92 ms and 2=337.8±28.9 ms for 2-week Epi, and iii) 1=73.4±3.52 ms and 2=546.3±38.6ms for 5-week Epi. In 2-week paced dogs, NS5806 increased Ito (at +50 mV) from 16.12±1.4 pA/pF to 23.85±2.1 pA/pF (p<0.05). In 5-week paced dogs, application of NS5806 increased Ito from 10.69±1.4 pA/pF to 14.35±1.9 pA/pF (p<0.05). In the presence of NS5806, both the fast and slow phase of Ito recovery increased in 2 and 5-week paced cells. Application of NS5806 to HF wedges restored phase 1 repolarization. Conclusions: HF produces a time dependent reduction in the size of Ito and a slowing in recovery from inactivation. Application of an Ito agonist to HF cells increased the magnitude of Ito and rate of Ito recovery. In HF wedge preparations, 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.