Calcium paradox of aldosteronism and the role of the parathyroid glands

Abstract

The hypercalciuria and hypermagnesuria that accompany aldosteronism contribute to a fall in plasma ionized extracellular Ca2+ and Mg2+ concentrations ([Ca2+]o and [Mg2+]o). Despite these losses and the decline in extracellular levels of these cations, total intracellular and cytosolic free Ca2+ concentration ([Ca2+]i) is increased and oxidative stress is induced. This involves diverse tissues, including peripheral blood mononuclear cells (PBMC) and plasma. The accompanying elevation in plasma parathyroid hormone (PTH) and reduction in bone mineral density caused by aldosterone (Aldo)-1% NaCl treatment (AldoST) led us to hypothesize that Ca2+ loading and altered redox state are due to secondary hyperparathyroidism (SHPT). Therefore, we studied the effects of total parathyroidectomy (PTx). In rats receiving AldoST, without or with a Ca2+-supplemented diet and/or PTx, we monitored urinary Ca2+ and Mg2+ excretion; plasma [Ca2+]o, [Mg2+]o, and PTH; PBMC [Ca2+]i and H2O2 production; plasma alpha1-antiproteinase activity; total Ca2+ and Mg2+ in bone, myocardium, and rectus femoris; and gp91(phox) labeling in the heart. We found that 1) the hypercalciuria and hypermagnesuria and decline (P < 0.05) in plasma [Ca2+]o and [Mg2+]o that occur with AldoST were not altered by the Ca2+-supplemented diet alone or with PTx; 2) the rise (P < 0.05) in plasma PTH with AldoST, with or without the Ca2+-supplemented diet, was prevented by PTx; 3) increased (P < 0.05) PBMC [Ca2+]i and H2O2 production, increased total Ca2+ in heart and skeletal muscle, and fall in bone Ca2+ and Mg2+ and plasma alpha1-antiproteinase activity with AldoST were abrogated (P < 0.05) by PTx; and 4) gp91(phox) activation in right and left ventricles at 4 wk of AldoST was attenuated by PTx. AldoST is accompanied by SHPT, with parathyroid gland-derived calcitropic hormones being responsible for Ca2+ overload in diverse tissues and induction of oxidative stress. SHPT plays a permissive role in the proinflammatory vascular phenotype.