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

Abstract 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. NS 5806 has been identified as a prototypic activator of canine I to . This study investigated, for the first time, actions of NS 5806 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  μ mol/L NS 5806 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 EC 50 for stimulation was 1.6  μ mol/L and inhibition had an IC 50 of 40.7  μ mol/L. NS 5806 only inhibited atrial I to ( IC 50 of 18  μ mol/L) and produced a modest leftward shifts in I to activation and inactivation, without an effect on restitution. 10  μ mol/L NS 5806 shortened ventricular action potential duration ( APD ) at APD 20 ‐ APD 90 but prolonged atrial APD . NS 5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio‐selective effect on Na + channels. In contrast to NS 5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I to . NS 5806 discriminates between rabbit ventricular and atrial I to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS 5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I to .