# NaV1.5 or KCa2 channel blockade does not increase arrhythmia risk in hypokalemic rabbit hearts, unlike KV11.1 inhibition with dofetilide

## TL;DR

This study shows that blocking KCa2 channels or NaV1.5 in rabbit hearts does not increase arrhythmia risk, unlike blocking KV11.1 with dofetilide.

## Contribution

The study reveals that KCa2 channel blockade is not pro-arrhythmic in rabbit hearts, unlike KV11.1 inhibition.

## Key findings

- KCa2 channel inhibitors did not prolong ventricular action potential duration or increase arrhythmia risk.
- Dofetilide prolonged APD and increased arrhythmia susceptibility in hypokalemic conditions.
- KCa2 channels appear to have minimal role in ventricular repolarization under normal and low potassium conditions.

## Abstract

The small conductance calcium activated potassium channel (KCNN1-3; KCa2.1–3) is recognized as a possible new anti-arrhythmic drug target for treatment of atrial fibrillation (AF). The aim of this study is to investigate potential ventricular effects of KCa2 channel inhibition under normal, bradycardic and hypokalemic conditions and compare these to classical class I and III anti-arrhythmic drugs.

Rabbit hearts were isolated, AV-ablated, mounted in an ex vivo Langendorff preparation and perfused with normokalemic (4 mM K+) Krebs-Henseleit solution, followed by perfusion with drug (AP14145 3 µM; AP30663 1.5 µM; dofetilide 10 nM; flecainide 1.5 µM) or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug. Changes in ventricular action potential duration were assessed by monophasic action potential recordings. Neither of the KCa2 channel inhibitors (AP14145 or AP30663) or flecainide (NaV1.5 inhibitor) prolonged ventricular action potential duration (APD90) or increased pro-arrhythmic markers, whereas dofetilide (KV11.1 blocker) prolonged APD and increased the susceptibility to ventricular arrhythmia.

These findings suggests that KCa2 channels have minimal importance for ventricular repolarization in healthy rabbit hearts under both normo- and hypokalemic conditions.