TY - JOUR

T1 - Antiarrhythmic effect of IKr activation in a cellular model of LQT3

AU - Diness, Jonas Goldin

AU - Hansen, Rie Schultz

AU - Nissen, Jakob Dahl

AU - Jespersen, Thomas

AU - Grunnet, Morten

N1 - Keywords: Action Potentials; Animals; Chloride Channels; Disease Models, Animal; Female; Guinea Pigs; Heart Ventricles; Ion Channel Gating; Long QT Syndrome; Myocytes, Cardiac; Patch-Clamp Techniques; Phenylurea Compounds; Potassium Channels; Sodium Channels; Tetrazoles

PY - 2008

Y1 - 2008

N2 - BACKGROUND: Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients. OBJECTIVE: The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II. METHODS: Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C. RESULTS: NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation. CONCLUSION: The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.

AB - BACKGROUND: Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients. OBJECTIVE: The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II. METHODS: Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C. RESULTS: NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation. CONCLUSION: The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.

U2 - 10.1016/j.hrthm.2008.10.020

DO - 10.1016/j.hrthm.2008.10.020

M3 - Journal article

C2 - 19121808

VL - 6

SP - 100

EP - 106

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 1

ER -