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 mu M) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 mu M) 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 mu M) 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 mu M) 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 INa in both cell types. Expression of mRNA encoding putative INa and I-to channel subunits was evaluated by qPCR. Conclusion: NS5806 produces a prominent augmentation of I-to with little effect on INa in the ventricles, but a potent inhibition of INa with little augmentation of I-to in atria. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1057-1066, September 2011)