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(Circulation. 2005;111:51-57.)
© 2005 American Heart Association, Inc.

Heart Failure

Aldosteronism and a Proinflammatory Vascular Phenotype

Role of Mg²⁺, Ca²⁺, and H₂O₂ in Peripheral Blood Mononuclear Cells

Robert A. Ahokas, PhD; Yao Sun, MD, PhD; Syamal K. Bhattacharya, PhD; Ivan C. Gerling, PhD; Karl T. Weber, MD

From the Departments of Obstetrics and Gynecology (R.A.A.), Surgery (S.K.B.), and Divisions of Cardiovascular Diseases (Y.S., K.T.W.) and Endocrinology and Metabolism (I.C.G.), Department of Medicine, University of Tennessee Health Science Center, Memphis, Tenn.

Correspondence to Karl T. Weber, MD, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 920 Madison Ave, Suite 300, Memphis, TN 38163. E-mail KTWeber{at}utmem.edu

Received August 5, 2004; revision received September 10, 2004; accepted September 29, 2004.

Background— Chronic, inappropriate (relative to dietary Na⁺) elevations in circulating aldosterone, such as occur in congestive heart failure, are accompanied by a proinflammatory vascular phenotype involving the coronary and systemic vasculature. An immunostimulatory state with activated peripheral blood mononuclear cells (PBMCs) precedes this phenotype and is induced by a fall in cytosolic free [Mg²⁺]_i and subsequent Ca²⁺ loading of these cells and transduced by oxidative/nitrosative stress.

Methods and Results— We sought to further validate this hypothesis in rats with aldosterone/1%NaCl treatment (ALDOST) by using several interventions as cotreatment: a Mg²⁺-supplemented diet; amlodipine, a CCB; and N-acetylcysteine, an antioxidant. Blood samples were obtained at weeks 1 to 4 of ALDOST to monitor [Mg²⁺]_i, [Ca²⁺]_I, and H₂O₂ production in PBMCs. Coronal ventricular sections were examined for invading inflammatory cells and 3-nitrotyrosine labeling, a marker of oxidative/nitrosative stress. In response to ALDOST and compared with untreated controls, we found an early and persistent reduction in [Mg²⁺]_i with a subsequent rise in [Ca²⁺]_i and H₂O₂ production, each of which was either attenuated or abrogated by the Mg²⁺-supplemented diet and by N-acetylcysteine, whereas amlodipine prevented Ca²⁺ loading and an altered redox state. Cotreatment with these interventions either markedly attenuated or prevented the appearance of the proinflammatory coronary vascular phenotype and the presence of 3-nitrotyrosine in invading inflammatory cells.

Conclusions— We suggest that the immunostimulatory state that appears during aldosteronism and leads to a proinflammatory coronary vascular phenotype is induced by a fall in [Mg²⁺]_i with Ca²⁺ loading of PBMCs and is transduced by H₂O₂ production in these cells.

Key Words: calcium • stress • pathology • aldosterone • magnesium

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