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

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