Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806

Transient outward potassium current (I_to) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of I_to may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I_to This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I_to Whole cell patch-clamp recordings of I_to and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μmol/L NS5806 increased ventricular I_to with a leftward shift in I_to activation and accelerated restitution. At higher concentrations, stimulation of I_to was followed by inhibition. The EC₅₀ for stimulation was 1.6 μmol/L and inhibition had an IC₅₀ of 40.7 μmol/L. NS5806 only inhibited atrial I_to (IC₅₀ of 18 μmol/L) and produced a modest leftward shifts in I_to activation and inactivation, without an effect on restitution. 10 μmol/L NS5806 shortened ventricular action potential duration (APD) at APD₂₀-APD₉₀ but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na⁺ channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I_to NS5806 discriminates between rabbit ventricular and atrial I_to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I_to.