Comparison of the Effects of a Transient Outward Potassium Channel Activator on Currents Recorded from Atrial and Ventricular Cardiomyocytes.

TY - JOUR

T1 - Comparison of the Effects of a Transient Outward Potassium Channel Activator on Currents Recorded from Atrial and Ventricular Cardiomyocytes.

AU - Callø, Kirstine

AU - Nof, Eyal

AU - Jespersen, Thomas

AU - Di Diego, José M

AU - Chlus, Natalie

AU - Olesen, Søren-Peter

AU - Antzelevitch, Charles

AU - Cordeiro, Jonathan M

N1 - © 2011 Wiley Periodicals, Inc.

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

KW - Action Potentials

KW - Animals

KW - Dogs

KW - Female

KW - Heart Atria

KW - Heart Ventricles

KW - Male

KW - Myocytes, Cardiac

KW - Phenylurea Compounds

KW - Potassium Channels

KW - Tetrazoles

U2 - 10.1111/j.1540-8167.2011.02053.x

DO - 10.1111/j.1540-8167.2011.02053.x

M3 - Journal article

C2 - 21457383

SN - 1045-3873

VL - 22

SP - 1057

EP - 1066

JO - Journal of Cardiovascular Electrophysiology

JF - Journal of Cardiovascular Electrophysiology

IS - 9

ER -