Effects of class III anti-arrhythmic agents with hERG channel block and facilitation on cardiac action potential: a simulation study.

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]