{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:38:47Z","timestamp":1791092327977,"version":"4.1.0"},"reference-count":40,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2007,11]]},"abstract":"<jats:p>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<jats:sub>f<\/jats:sub>) 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\u201324 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. I<jats:sub>f<\/jats:sub>current elicited by hyperpolarization from \u221250 to \u2212130 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 \u03bcM eplerenone or 0.1 \u03bcM spironolactone) abolish the increase of I<jats:sub>f<\/jats:sub>channel expression (currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 \u03bcM aldosterone downregulated I<jats:sub>f<\/jats:sub>channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of I<jats:sub>f<\/jats:sub>current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates I<jats:sub>f<\/jats:sub>channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions.<\/jats:p>","DOI":"10.1152\/ajpheart.01399.2006","type":"journal-article","created":{"date-parts":[[2007,7,21]],"date-time":"2007-07-21T00:44:26Z","timestamp":1184978666000},"page":"H2710-H2718","source":"Crossref","is-referenced-by-count":27,"title":["Aldosterone modulates<i>I<\/i><sub>f<\/sub>current through gene expression in cultured neonatal rat ventricular 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