Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes

Effect of NS5806 on Atrial Currents. Introduction: NS5806 activates the transient outward potassium current (I _to) in canine ventricular cells. We compared the effects of NS5806 on canine atrial versus ventricular tissues and myocytes. Methods and Results: NS5806 (10 μM) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 μM) accentuated phase 1 in epicardium (Epi), with little effect in endocardium (Endo), resulting in augmented J-waves on the ECG. In contrast, application of NS5806 (10 μM) to atrial preparations had no effect on phase 1 repolarization but significantly decreased upstroke velocity (dV/dt) and depressed excitability, consistent with sodium channel block. Current and voltage-clamp recordings were made in the absence and presence of NS5806 in (10 μM) enzymatically dissociated atrial and ventricular myocytes. In ventricular myocytes, NS5806 increased I _to magnitude by 80% and 16% in Epi and Endo, respectively (at +40 mV). In atrial myocytes, NS5806 increased peak I _to by 25% and had no effect on the sustained current, I _Kur. Under control conditions, I _Na density in atrial myocytes was nearly double that in ventricular myocytes. NS5806 caused a shift in steady-state mid-inactivation (V _1/2) from -73.9 ± 0.27 to -77.3 ± 0.21 mV in ventricular and from -82.6 ± 0.12 to -85.1 ± 0.11 mV in atrial cells, resulting in reduction of I _Na in both cell types. Expression of mRNA encoding putative I _Na and I _to channel subunits was evaluated by qPCR. Conclusion: NS5806 produces a prominent augmentation of I _to with little effect on I _Na in the ventricles, but a potent inhibition of I _Na with little augmentation of I _to in atria.