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

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 (I), and transient potassium (I) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking I. Dose-response analysis indicated that 2Nal acts as a partial antagonist of I, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting I. Our lab previously found that an imbalance between I and I 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 I blockers are cardiotoxic. The selective blockade of I by 2Nal that we describe here helps restore the balance of electrical currents between I and I. Our study presents a novel, safe partial antagonist of I that may help prevent arrhythmias associated with Brugada syndrome.