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Potassium channels encoded by human ether-a-go-go-related gene (hERG) underlie the rapidly activating component of the delayed rectifying potassium current (IKr) in heart and play an important role in terminating the cardiac action potential (AP) (Sanguinetti & Tristani-Firouzi, 2006). hERG channel has been shown to be the target of class III anti-arrhythmic agents. It has also become clear that hERG channel is blocked by compounds with high pro-arrhythmic risk. The unintended block of hERG channel causes an acquired form of QT interval prolongation, worsens transmural dispersion of repolarization and forms the substrate for generation of life-threatening cardiac arrhythmias, including torsades de pointes. Recently, we have experimentally demonstrated a dual effect of some anti-arrhythmic agents, such as nifekalant, on hERG channel (Hosaka et al., 2007; Furutani et al., 2011). Besides blocking hERG channel, these compounds can facilitate its activation. To assess the clinical relevance of hERG channel modulations by compounds, we conducted simulations of cardiac AP in a modified Luo-Rudy model with hERG channel block and facilitation, using our experimental data of nifekalant. Then, we found that the hERG channel block prolonged action potential duration (APD) in the block conditions both with and without facilitation. In addition, the refractory period in both conditions equally increased from control condition so that the ectopic cell excitation is suppressed, suggesting that even if hERG channel blocker has facilitation effect, anti-arrhythmic efficacy of the drug is equivalent to that of pure blocker. As in our simulation, we could observe an early afterdepolarization (EAD) when both IKr and the slowly activating component of the delayed rectifying potassium current (IKs) were blocked. Importantly, facilitation mechanism prevents hazardous prolongation of APD and the induction of EAD by accelerating the repolarization rate via an increase in IKr during prolonged phase 3. Therefore, anti-arrhythmic agents that has both block and facilitation effects on hERG channel may have a lower risk for inducing EADs and triggered activity and thus be more suitable forthe treatment of arrhythmias than pure hERG blocker. Sanguinetti MC and Tristani-Firouzi M (2006). Nature 440, 463-469. [ABSTRACT FROM AUTHOR]

Background: Na channel blockade has a long history used for the treatment of symptomatic ventricular premature contractions and tachycardia. However, the Cardiac Arrhythmia Suppression Trial(CAST) in patients with old myocardial infarction showed that class-I antiarrhythmic drugs have proarrhythmic effects, resulting in poor prognoses. So far, the arrhythmogenic mechanisms by the Na channel blockade are not well-known. Methods: To clarify this issue, we conducted simulations of action potential propagation in a myofiber model incorporating the electric field mechanism (taking into account the intercellular cleft potentials). Since it is recently reported that Na channels are confined to intercalated discs of surviving myocytes (lack of Na channels in lateral cell membrane) in the ischemic border zone, we incorporated the intra-cellular remodeling of Na channels into the model. Results: We found that the intracellular remodeling of Na channels in myocytes located at ischemic border zone contributed to conduction slowing. In addition, conduction block tended to occur in the ischemic border zone when numerically administered Na channel blockade to the myofiber model, but this was not the case when the Na channels were distributed over the entire cell membrane. Conclusion: Ischemia-induced intracellular remodeling of Na channels might be partly responsible for the proarrhythmic effects of Na channel blockade in patients with old myocardial infarction. [ABSTRACT FROM AUTHOR]