Hormonal Control of Cardiac Action Potential Phase 1 Currents in the Brugada Syndrome

Mariana Argenziano, Gisela Tiscornia, Rosalía Moretta, Carlos E. Amorena, Eduardo García Gras

Abstract


Introduction: The Brugada syndrome is an inherited channelopathy with autosomal dominant genotype transmission patternpresenting marked gender bias in phenotype expression, with a male to female ratio of 9:1. A cellular model of the diseasesuggests a heterogeneous distribution in the phase 1 amplitude of the ventricular action potential as the origin for the developmentof the arrhythmogenic substrate.

Objective: The aim of this study was to investigate the role of androgens on the cardiac action potential phase 1 regulationand its electrophysiological consequences in an experimental murine model of Brugada syndrome.

Methods: Androgen control of gene expression was studied in HL-1 cells and rat hearts using real time polymerase chainreaction (PCR). For the electrophysiological studies, an experimental model of the Brugada syndrome was reproduced in aLangendorff system using Tyrode solution supplemented with pinacidil and terfenadine.

Results: Treatment of HL-1 cells with di-hydro-testosterone increased the expression of the Kv4.3 potassium channel and thesodium/calcium exchanger (NCX). This effect was assessed in rats treated with testosterone and finasteride. The expressionof both genes decreased with finasteride, where as testosterone increased NCX messenger ribonucleic acid (mRNA) level.Testosterone produced action potential shortening at 90% repolarization (APD90) and decreased time to peak (TTP), whichin Brugada syndrome models correlate with increased arrhythmogenesis. In our model, this phenomenon was observed bothas an increase of sporadic and sustained ectopic ventricular action potentials. The frequency of ectopic action potentials inducedwith terfenadine and pinacidil in the control group was reduced by an order of magnitude with finasteride treatment.

Conclusions: Androgens control the expression of key components of the cardiac action potential resulting in increased arrhythmogenesis.Finasteride treatment reverses these effects.


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Revista argentina de cardiología. ISSN en línea 1850-3748. Argentine journal of cardiology (English ed. Online ISSN 2314-2286) Sociedad Argentina de Cardiología. Azcuénaga 980 (C1115AAD),Ciudad Autónoma de Buenos Aires, República Argentina. Tel. (54 11) 4961-6027/8/9 Fax: 4961-6020 www.sac.org.ar revista@sac.org.ar