Aldosteronism and a proinflammatory vascular phenotype: role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells.

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.