title: Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone.
abstract: Zinc is a structural constituent of many proteins, including Cu/Zn superoxide dismutase (SOD), an endogenous antioxidant enzyme. Hypozincemia has been found in patients hospitalized with congestive heart failure, where neurohormonal activation, including the renin-angiotensin-aldosterone system (RAAS), is expected and oxidative stress is present. This study was undertaken to elucidate potential pathophysiological mechanisms involved in Zn dyshomeostasis in aldosteronism. In rats receiving aldosterone/salt treatment (ALDOST) alone for 1 and 4 wk or in combination with spironolactone (Spiro), an ALDO receptor antagonist, we monitored 24-h urinary and fecal Zn excretion and tissue Zn levels in heart, liver, and skeletal muscle, together with tissue metallothionein (MT)-I, a Zn(2+)-binding protein, and Cu/Zn-SOD activities in plasma and tissues. When compared with unoperated, untreated, age-/sex-matched controls, urinary and, in particular, fecal Zn losses were markedly increased (P < 0.05) at days 7 and 28 of ALDOST, leading to hypozincemia and a fall (P < 0.05) in plasma Cu/Zn-SOD activity. Microscopic scars and perivascular fibrosis of intramural coronary arteries first appeared in the right and left ventricles at week 4 of ALDOST and were accompanied by increased (P < 0.05) tissue Zn, MT-I, and Cu/Zn-SOD activity, which were not found in uninjured liver or skeletal muscle. Spiro cotreatment prevented cardiac injury and Zn redistribution to the heart. Thus increased urinary and fecal Zn losses, together with their preferential translocation to sites of cardiac injury, where MT-I overexpression and increased Cu/Zn-SOD activity appeared, contribute to Zn dyshomeostasis in rats with aldosteronism, which were each prevented by Spiro. These findings may shed light on Zn dyshomeostasis found in patients with decompensated heart failure.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Manesh
authors.initials: M
authors.lastname: Thomas
authors.forename: Alex
authors.initials: A
authors.lastname: Vidal
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Gerling
authors.forename: Karl T
authors.initials: KT
authors.lastname: Weber
mesh_terms: D000450:Aldosterone; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D005355:Fibrosis; D006706:Homeostasis; D006929:Hyperaldosteronism / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008668:Metallothionein / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000097:blood / Q000172:deficiency / Q000378:metabolism* / Q000652:urine
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; C491055:Mt2A protein, rat; D013148:Spironolactone; D000450:Aldosterone; D008668:Metallothionein; D013482:Superoxide Dismutase; D015032:Zinc