Comparison of the Effects of the Transient Outward Potassium Channel Activator NS5806 on Canine Atrial and Ventricular Cardiomyocytes

Abstract

Objective: NS5806 activates the transient outward potassium current (Ito) in canine ventricular cells. We compared the effects of NS5806 on canine ventricular versus atrial tissues and myocytes. Methods: NS5806 (10 μM) was evaluated in arterially-perfused canine right atrial and left ventricular wedges. Atrial and ventricular epi- and endocardial cells were isolated by enzymatic dissociation. Current and voltage-clamp recordings were made in the absence and presence of NS5806. Results: In ventricular wedges NS5806 increased phase 1 repolarization in epi- and midmyocardial cells. A minor effect on conduction and upstroke velocity also was observed. In contrast, application of NS5806 to atrial preparations slowed upstroke velocity and reduced excitability, consistent with sodium channel block. In ventricular myocytes, NS5806 increased the magnitude of Ito by 80% and 16% in epi and endo, respectively (at +40 mV). In atrial myocytes, NS5806 increased peak Ito by 25% and had no effect on the sustained pedestal current, IKur. INa density in atrial myocytes was nearly 100% greater than in endocardial myocytes. NS5806 caused a negative shift in steady-state mid-inactivation (V1/2) for both cell types (73.9±0.27 to −77.3±0.21mV for endocardial and −82.6±0.12 to −85.1±0.11mV for atrial cells). The shift in V1/2 resulted in a reduction of INa in both cell types. However, the more negative V1/2 in atrial cells suggests that atrial cells lose excitability at more depolarized voltages than endocardial cells which may explain the greater reduction of excitability in atrial vs ventricular wedges by NS5806. Conclusion: NS5806 produces a prominent augmentation of Ito with little effect on INa in the ventricles, but a potent inhibition of INa with little augmentation of Ito in atria.