title: Direct effects of aldosterone on cardiomyocytes in the presence of normal and elevated extracellular sodium.
abstract: 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 (3)H-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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamamuro
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakayama
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Makoto
authors.initials: M
authors.lastname: Shono
authors.forename: Satoru
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yasue
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002478:Cells, Cultured; D000077545:Eplerenone; D006439:Hemodynamics; D006984:Hypertrophy; D007211:Indoles / Q000494:pharmacology; D007930:Leucine / Q000737:chemistry / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors
chemical_list: D000577:Amides; D001572:Benzofurans; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; D010795:Phthalic Acids; C401341:SM 20220; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C059768:isophthalate; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D012964:Sodium; D007930:Leucine; C105430:benzofuran