Purpose Aldosteronism, or inappropriate (relative to dietary Na+) elevations in plasma aldosterone (ALDO), such as occur in congestive heart failure (CHF), is accompanied by a proinflammatory phenotype involving diverse tissues, including immune cells and the heart. Herein we hypothesized that Ca2+ loading of these cells is the inducer and oxi/nitrosative stress the transducer of cell activation and which is mediated by elevations in parathyroid hormone (PTH) that appear due to the hypercalciuria and hypermagnesuria that accompany aldosteronism.
Methods Uninephrectomized rats received ALDO/salt treatment (ALDOST, 0.75 μg/h + dietary 1% NaCl/0.4% KCl) alone or in combination with either amlodipine, a Ca2+ channel blocker (CCB, 10 mg/day by gavage), or N-acetylcysteine, an antioxidant (NAC, 200 mg/kg qd ip). Age-/gender-matched, untreated animals served as controls. At 4 weeks treatment, we monitored cytosolic-free [Ca2+]i in peripheral blood mononuclear cells (PBMC); lymphocyte H2O2 production; 3-nitrotyrosine labeling in coronal sections of biventricular tissue; and plasma PTH.
Results At 4 weeks ALDOST and compared to controls, we found a rise in PBMC [Ca2+]i (76.4 ± 12.6 vs. 45.9 ± 2.4 nmol/L; p < .05); elevated lymphocyte H2O2 production (247.9 ± 17.7 vs. 96.8 ± 6.4 MCB; p < .05); an invasion of right and left ventricular tissue by inflammatory cells expressing 3-nitrotyrosine; and elevated plasma PTH (29.2 ± 7.44 vs. 10.9 ± 3.2 pmol/mL; p < .05). CCB and NAC each prevented PBMC Ca2+ loading and associated rise in H2O2 production and each attenuated the appearance of 3-nitrotyrosine-positive inflammatory cells in cardiac tissue.
Conclusions The proinflammatory phenotype that appears in aldosteronism is induced by Ca2+ loading of PBMC and is transduced by oxi/nitrosative stress. Secondary hyperparathyroidism is responsible for immune cell activation due to paradoxical intracellular Ca2+ loading, which can be prevented by reducing Ca2+ entry through channel blockade and/or antioxidant.