# A Metabolically Stable Apelin-13 Analog Acting as a Potent ITo Potassium Current Blocker with Potential Benefits for Brugada Syndrome

## TL;DR

A new apelin analog selectively blocks potassium currents in heart cells, potentially offering a treatment for Brugada syndrome.

## Contribution

A metabolically stable apelin analog is introduced as a selective ITo blocker with potential therapeutic benefits for Brugada syndrome.

## Key findings

- 2Nal partially blocks ITo currents with an EC50 of 0.3 nM and a maximum blockade of 47%.
- 2Nal prolongs ventricular action potential duration without affecting INa currents.
- 2Nal may restore the ITo-INa current balance disrupted in Brugada syndrome.

## Abstract

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (INa), and transient potassium (ITO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking ITo. Dose-response analysis indicated that 2Nal acts as a partial antagonist of ITO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting INa. Our lab previously found that an imbalance between ITo and INa currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most ITo blockers are cardiotoxic. The selective blockade of ITo by 2Nal that we describe here helps restore the balance of electrical currents between ITo and INa. Our study presents a novel, safe partial antagonist of ITo that may help prevent arrhythmias associated with Brugada syndrome.