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

摘要

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 muM) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 muM) 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 muM) 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 muM) 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.