Zinc is a structural constituent of many proteins, including Cu/Zn superoxide dismutase (SOD), an endogenous antioxidant enzyme. Hypozincemia has been found in patients 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 pathophysiologic mechanisms involved in Zn dyshomeostasis in aldosteronism. In rats receiving aldosterone/salt treatment (ALDOST) alone for 1 and 4 wks or in combination with spironolactone (Spiro), an ALDO receptor antagonist, we monitored 24-hr urinary and fecal Zn excretion and tissue Zn levels in heart, liver and skeletal muscle, together with tissue metallothionein (MT)-I, a Zn²⁺-binding protein, and Cu/Zn-SOD activities in plasma and tissues. Compared to unoperated, untreated, age-/gender-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 wk 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 its 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 and which were each prevented by Spiro. These findings may shed light on Zn dyshomeostasis found in patients with decompensated heart failure.