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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H2710    most recent 01399.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Muto, T. Articles by Yasui, K. Search for Related Content PubMed PubMed Citation Articles by Muto, T. Articles by Yasui, K.

Aldosterone modulates I_f current through gene expression in cultured neonatal rat ventricular myocytes

¹Research Institute of Environmental Medicine, Department of Bio-information Analysis, Nagoya University, Nagoya, Japan; ²Experimental Cardiology Group, Center for Heart Failure Research, Academic Medical Center, Amsterdam, the Netherlands; ³Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands; ⁴Yamaguchi University School of Medicine, Yamaguchi, Japan; ⁵Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan; and ⁶Research Institute of Environmental Medicine, Department of Cardiovascular Research, Nagoya University, Nagoya, Japan

Submitted 21 December 2006 ; accepted in final form 17 July 2007

Mineralocorticoid receptor (MR) antagonists decrease the incidence of sudden cardiac death in patients with heart failure, as has been reported in two clinical trials (Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). Aldosterone has been shown to increase the propensity to arrhythmias by changing the expression or function of various ion channels. In this study, we investigate the effect of aldosterone on the expression of hyperpolarization-activated current (I_f) channels in cultured neonatal rat ventricular myocytes, using the whole cell patch-clamp technique, real-time PCR, and Western blotting. Incubation with 10 nM aldosterone for 17–24 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. I_f current elicited by hyperpolarization from –50 to –130 mV significantly increases aldosterone by 10 nM (by 1.9-fold). Exposure to aldosterone for 1.5 h increases hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 mRNA by 26.3% and HCN4 mRNA by 47.2%, whereas HCN1 mRNA expression remains unaffected. Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein. MR antagonists (1 µM eplerenone or 0.1 µM spironolactone) abolish the increase of I_f channel expression (currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 µM aldosterone downregulated I_f channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of I_f current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates I_f channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions.

eplerenone; spironolactone; automaticity; arrhythmia; HCN gene