title: Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism.
abstract: Iterations in Ca2+ and Mg2+ balance accompany aldosteronism (inappropriate for dietary Na+ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined. (1) To study the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO3 excretion. (2) To assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn2+]i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress were examined. (3) Oxidative stress and cardiac pathology in response to ZnSO4 supplement (40 mg/d) were also studied. Comparison of controls and rats receiving 4 weeks ALDOST revealed the following: (1) an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; (2) a rise in cardiac Zn, including increased [Zn2+]i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91(phox), coupled with oxidative stress in plasma and urine; (3) ZnSO4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO4 attenuated cardiomyocyte necrosis; however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contributes to cardiac pathology.
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Malay S
authors.initials: MS
authors.lastname: Gandhi
authors.forename: Prajwal A
authors.initials: PA
authors.lastname: Deshmukh
authors.forename: German
authors.initials: G
authors.lastname: Kamalov
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Whaley
authors.forename: Jill R
authors.initials: JR
authors.lastname: Tichy
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: D000086:Acetazolamide / Q000494:pharmacology; D000450:Aldosterone; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D006929:Hyperaldosteronism / Q000503:physiopathology*; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000188:drug therapy / Q000209:etiology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*; D019287:Zinc Sulfate / Q000494:pharmacology*
chemical_list: D000450:Aldosterone; D019287:Zinc Sulfate; D008668:Metallothionein; D008274:Magnesium; D015032:Zinc; D000086:Acetazolamide; D002118:Calcium