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Direct Effects of Aldosterone on Cardiomyocytes in the Presence of Normal and Elevated Extracellular Sodium

Department of Cardiovascular Medicine (Me.Y., Mi.Y., M.N., K.A., M.S., S.S., T.S., H.O.), Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; First Department of Internal Medicine (Y.S.), Nara Medical University, Nara 634-8521, Japan; Department of Medicine and Clinical Science (K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; and Division of Cardiology (H.Y.), Kumamoto Aging Research Institute, Kumamoto 860-8518, Japan

Address all correspondence and requests for reprints to: Michihiro Yoshimura, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: bnp{at}kumamoto-u.ac.jp.

It is now recognized that aldosterone is potentially cardiotoxic, although its local effects in the heart are not well understood. We examined the effects of aldosterone on cultured neonatal rat cardiomyocytes in the presence of normal and elevated extracellular Na⁺ ([Na⁺]_o). We evaluated the intracellular volume of cardiomyocytes in the presence of normal (141 mEq/liter) and elevated (146 mEq/liter) [Na⁺]_o by measuring cell size. Intracellular Na⁺ was measured using sodium-binding-benzofuran-isophthalate as a fluorescent sodium indicator, and cardiac hypertrophy was assessed using B-type natriuretic peptide transcription and ³H-leucine incorporation. Cardiomyocytes shrank in the presence of 146 mEq/liter Na⁺ due to the increased extracellular osmolarity at early phase. Aldosterone (10^–7 mol/liter) mitigated the shrinkage by stimulating Na⁺ uptake by the cells. This effect of aldosterone was blocked by SM 20220, a Na⁺/H⁺ exchanger 1 (NHE1) inhibitor, but not by eplerenone, a mineralocorticoid receptor blocker. Seventy-two hours of exposure to aldosterone in the presence of 146 mEq/liter Na⁺ led to increases in cardiomyocyte size, ³H-leucine incorporation, and B-type natriuretic peptide and NHE1 transcription that were significantly greater than were seen in the presence of 141 mEq/liter Na⁺. All but the last were blocked by either eplerenone or SM 20220; the increase in NHE1 transcription was blocked only by eplerenone. Aldosterone exerts a beneficial effect via NHE1 to block cardiomyocyte shrinkage in the presence of elevated [Na⁺]_o at early phase, but long-time exposure to aldosterone in the presence of elevated [Na⁺]_o leads to cardiomyocyte hypertrophy via genomic effects mediated by the mineralocorticoid receptor.

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