Published Online
on December 20, 2004

A more recent version of this article appeared on January 4, 2005

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Submitted on August 5, 2004
Revised on September 10, 2004
Accepted on September 29, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: KTWeber{at}utmem.edu.

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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