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Aldosterone Inhibits Inducible Nitric Oxide Synthase in Neonatal Rat Cardiomyocytes

Department of Medicine (T.-Y.C., J.H.P.) and the Veterans Affairs Medical Center (J.H.P.), Indiana University Medical School, Indianapolis, Indiana 46202; and Lilly Research Laboratories (L.J.B.), Eli Lilly and Co., Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Tae-Yon Chun, Ph.D., Department of Medicine, 541 Clinical Drive, Room 458, Indianapolis, Indiana 46202. E-mail: tchun{at}iupui.edu.

In studies of animals, increases in aldosterone are associated with myocardial necrosis and fibrosis, and treatment with spironolactone, an antagonist of aldosterone, improved clinical outcomes in patients with heart failure. In the present study, we explored nitric oxide (NO), a signaling molecule involved in cardiac function, as a potential mediator of aldosterone’s effects on the heart. Levels of both inducible NO synthase (iNOS) and NO from isolated rat neonatal cardiomyocytes pretreated with IL-1 were found to be decreased with exposure to aldosterone or dexamethasone in a dose-dependent manner. Spironolactone increased iNOS expression and prevented inhibition by aldosterone, consistent with a mineralocorticoid receptor-mediated mechanism for iNOS down-regulation. Aldosterone had no effect on iNOS mRNA levels, indicating a posttranscriptional mechanism for the inhibition of iNOS. Neutralization of TGF-ß1 using a specific antibody reversed aldosterone-dependent iNOS and NO down-regulation. In summary, aldosterone inhibited IL-1- induced iNOS expression posttranscriptionally by a TGF-ß1-dependent mechanism. The decrease in NO synthesis could have relevance to known cardiac effects of aldosterone.

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