Aldosterone increases voltage-gated sodium current in ventricular myocytes

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Electrophysiology

Background:

• The role of aldosterone in heart failure (HF) pathogenesis is not fully understood.
• Aldosterone influences cardiac Ca(2+) and K(+) channels, impacting electrical remodeling.

Purpose of the Study:

• To investigate the effect of aldosterone on cardiac sodium current (I(Na)).
• To explore the molecular mechanisms and potential therapeutic interventions related to aldosterone's impact on cardiac electrophysiology.

Main Methods:

• Whole-cell patch-clamp technique on isolated adult mouse ventricular myocytes.
• Incubation with aldosterone, mineralocorticoid receptor antagonist (spironolactone), and glucocorticoid receptor antagonist (RU-38486).
• Quantitative RT-PCR and Western blot analysis for Na(v)1.5 and Ca(v)1.2 channel expression.

Main Results:

• Aldosterone significantly increased I(Na) density by 55% (1 microM) and 23% (10 nM) without altering biophysical properties.
• The aldosterone-induced I(Na) increase was blocked by actinomycin D, cycloheximide, and brefeldin A, indicating a protein synthesis-dependent mechanism.
• Spironolactone prevented the aldosterone effect, while RU-38486 did not, implicating the mineralocorticoid receptor.
• Action potential duration (APD) and L-type Ca(2+) current were upregulated in aldosterone-treated myocytes.
• No significant changes in Na(v)1.5 and Ca(v)1.2 mRNA or protein levels were observed.

Conclusions:

• Aldosterone upregulates cardiac I(Na) through a mineralocorticoid receptor-dependent pathway.
• This upregulation may contribute to electrical remodeling in heart failure.
• Spironolactone shows potential in reversing aldosterone-induced electrophysiological changes in HF.