Abstract 14243: The Apelin Mimetic Peptide (2Nal) Partially Inhibits the Transient Outward Potassium Current (Ito) in Rat Cardiomyocytes; a Potential Pharmacological Agent Against Brugada Syndrome

Abstract

Introduction: Brugada syndrome (BrS) is an inherited disease characterized by ventricular cardiac arrhythmias leading to sudden cardiac death. One potential cause for arrhythmias is a disruption of the balance between the depolarizing fast sodium inward current (I Na ) and its opposing transient outward currents (I to ) favoring a faster repolarization during phase one of the action potential (AP). Hypothesis: BrS is mainly associated with a reduction in I Na amplitude caused by dominant mutations in the gene SCN5A encoding cardiac sodium channels. However, recent studies have shown that gain-of-function mutations in KCND3, the gene encoding Kv4.3 channels, increase I to amplitude. Therefore, targeting I to to modulate the balance of current during phase one of the AP represents a promising therapeutic approach to BrS, Methods: We used Patch-Clamp technique to test the effect of 2Nal, a newly synthesized peptide derived from apelin, on I to in rat ventricular cardiomyocytes. Apelin is an endogenous neurotransmitter with strong inotropic effects on cardiac cells. Results: We found that apelin had no effect on I to . In contrast, 2Nal maximally inhibited 46.9% ± 3.4 (n=9) of I to with an IC 50 =0.29 nM but did not change its kinetics, thus indicating that 2Nal acts as a partial blocker. The voltage dependence of potassium channels availability was not modified, suggesting that 2Nal simply reduced the conductance of each channel contributing to I to . Conclusions: Because of its partial antagonist effect on ITo, 2Nal provide a safety margin that could be potentially useful for the treatment of Brugada syndrome.