Antiarrhythmic effect of IKr activation in a cellular model of LQT3.

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_v1.5. 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_v1.5, 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°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 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. [Copyright &y& Elsevier]