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Antiarrhythmic effect of IKr activation in a cellular model of LQT3

2008; Elsevier BV; Volume: 6; Issue: 1 Linguagem: Inglês

10.1016/j.hrthm.2008.10.020

1556-3871

Jonas Goldin Diness, Rie Schultz Hansen, Jakob D. Nissen, Thomas Jespersen, Morten Grunnet,

Ion channel regulation and function

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, Nav1.5. 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 Nav1.5, thereby closely mimicking the underlying cause of LQT3 in patients. Objective The hypothesis for this study was that activation of the IKr current could counteract the proarrhythmic effects of ATX-II. Methods Two different activators of IKr, 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 IKr 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°C to 35°C. Results NS3623 significantly shortened action potential duration at 90% repolarization (APD90) 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 APD90 as well as early afterdepolarizations and increased beat-to-beat variability. Two independent IKr activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (INaL) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective IKr activation. Conclusion The present data show the antiarrhythmic potential of selective IKr activation in a cellular model of the LQT3 syndrome. Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Nav1.5. 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 Nav1.5, thereby closely mimicking the underlying cause of LQT3 in patients. The hypothesis for this study was that activation of the IKr current could counteract the proarrhythmic effects of ATX-II. Two different activators of IKr, 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 IKr 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°C to 35°C. NS3623 significantly shortened action potential duration at 90% repolarization (APD90) 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 APD90 as well as early afterdepolarizations and increased beat-to-beat variability. Two independent IKr activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (INaL) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective IKr activation. The present data show the antiarrhythmic potential of selective IKr activation in a cellular model of the LQT3 syndrome.