Corticosteroids and aldose reductase inhibitor Epalrestat modulates cardiac action potential via Kvß1.1 (AKR6A8) subunit of voltage-gated potassium channel.

We previously demonstrated the role of Kvß1.1 subunit of voltage-activated potassium channel in heart for its sensory roles in detecting changes in NADH/NAD and modulation of ion channel. However, the pharmacological role for the association of Kvß1 via its binding to ligands such as cortisone and its analogs remains unknown. Therefore, we investigated the significance of Kvß1.1 binding to cortisone analogs and AR inhibitor epalrestat. In addition, the aldose reductase (AR) inhibitor epalrestat was identified as a pharmacological target and modulator of cardiac activity via binding to the Kvß1 subunit. Using a combination of ex vivo cardiac electrophysiology and in silico binding, we identified that Kvß1 subunit binds and interacts with epalrestat. To identify the specificity of the action potential changes, we studied the sensitivity of the action potential prolongation by probing the electrical changes in the presence of 4-aminopyridine and evaluated the specificity of pharmacological effects in the hearts from Kvß1.1 knock out mouse. Our results show that pharmacological modulation of cardiac electrical activity by cortisone analogs and epalrestat is mediated by Kvß1.1.