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Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish
Alicia De la Cruz1, Xiaoan Wu1, Quinn C Rainer1
1Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, FL 33136, USA.
Abstract:
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 IKs. 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 IKs analogues on the cardiac action potential. We found that chromanol 293B (an IKs inhibitor) prolonged the action potential duration (APD) in the presence of E4031 (an IKr 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 IKs activator, ML-277, partially reversed the APD prolongation in drug-induced LQT2 zebrafish hearts. Our results suggest that IKs plays a limited role in ventricular repolarizations in the zebrafish heart under resting conditions, although it plays a more important role when the IKr is compromised, as if the IKs in zebrafish serves as a repolarization reserve as in human hearts. This study shows that potent IKs activators can restore the action potential duration in drug-induced LQT2 in the zebrafish heart.
Insights
Zebrafish models reveal that IKs potassium channels are crucial for heart rhythm regulation, especially when other channels are compromised. Potent IKs activators can restore normal heart function in Long QT syndrome models.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Zebrafish as a Model Organism
Background:
- Long QT syndrome (LQTS) is a cardiac disorder associated with ventricular arrhythmias and sudden cardiac death.
- Mutations in the channel subunits of the cardiac potassium current IKs are a common cause of congenital LQTS.
- Zebrafish (Danio rerio) offer a valuable model for human cardiac diseases due to conserved cardiac electrical properties.
Purpose of the Study:
- To investigate the role of the IKs current in zebrafish cardiac action potential regulation.
- To assess the effects of IKs modulators on drug-induced Long QT syndrome (LQT2) in zebrafish.
- To evaluate zebrafish as a model for studying LQTS and potential therapeutic interventions.
Main Methods:
- High-resolution all-optical electrophysiology was performed on ex vivo zebrafish hearts.
- The effects of IKs inhibitors (chromanol 293B) and activators (ML-277) were assessed.
- Drug-induced LQT2 was modeled using E4031 (an IKr inhibitor) to examine IKs function under compromised conditions.
Main Results:
- Chromanol 293B prolonged action potential duration (APD) in zebrafish hearts, particularly when IKr was inhibited.
- PUFA analogues showed minimal effect on APD and did not reverse LQT2-induced prolongation.
- The potent IKs activator ML-277 partially reversed APD prolongation in drug-induced LQT2 zebrafish hearts.
Conclusions:
- The IKs current plays a significant role in ventricular repolarization reserve in zebrafish, especially when IKr is compromised, mirroring its function in humans.
- IKs activators demonstrate potential for restoring normal cardiac action potential duration in LQT2 models.
- This study validates the utility of zebrafish electrophysiology for studying cardiac ion channel function and LQTS.
