Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart

Long QT syndrome (LQTS) can lead to ventricular arrhythmia and sudden cardiac death. The most common congenital cause of LQTS is mutations in the channel subunits generating the cardiac potassium current I_Ks. Zebrafish (Danio rerio) have been proposed as a powerful system to model human cardiac diseases due to the similar electrical properties of the zebrafish heart and the human heart. We used high-resolution all-optical electrophysiology on ex vivo zebrafish hearts to assess the effects of I_Ks analogues on the cardiac action potential. We found that chromanol 293B (an I_Ks inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an I_Kr inhibitor applied to drug-induced LQT2), and to a lesser extent, in the absence of E4031. Moreover, we showed that PUFA analogues slightly shortened the APD of the zebrafish heart. However, PUFA analogues failed to reverse the APD prolongation in drug-induced LQT2. However, a more potent I_Ks activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that I_Ks plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the I_Kr is compromised, as if the I_Ks in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent I_Ks activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.