Cinacalcet and the prevention of secondary hyperparathyroidism in rats with aldosteronism

In rats receiving aldosterone/salt treatment (ALDOST), increased Ca2+ excretion leads to a fall in plasma-ionized Ca2+ and appearance of secondary hyperparathyroidism (SHPT) with parathyroid hormone (PTH)-mediated intracellular Ca2+ overloading inducing oxidative stress in diverse tissues. Parathyroidectomy prevents this scenario. Rats with ALDOST were cotreated with cinacalcet (Cina), a calcimimetic that raises the threshold of the parathyroids' Ca(2+)-sensing receptor.

We monitored plasma-ionized [Ca2+]o, PTH, and total Ca2+ in heart and peripheral blood mononuclear cells (PBMC), and evidence of oxidative stress in heart, PBMC, and plasma. Cina-treated rats for 4 weeks were compared with 4 weeks of ALDOST alone and with untreated age-/gender-matched controls. In comparison to controls, ALDOST led to a fall (P < 0.05) in Ca2+ (1.16 +/- 0.01 vs 1.03 +/- 0.01 mmol/L), which was not prevented by Cina (1.01 +/- 0.03 mmol/L); a rise (P < 0.05) in plasma PTH (36 +/- 7 vs 134 +/- 19 pg/mL) that was attenuated by Cina (69 +/- 12 pg/mL); increased (P < 0.05) cardiac [Ca2+] (3.92 +/- 0.25 vs 6.78 +/- 0.35 nEq/mg FFDT) and PBMC [Ca2+]i (29.8 +/- 2.3 vs 50.2 +/- 2.3 nmol/L), each of which was prevented with Cina (3.65 +/- 0.10 nEq/mg FFDT and 32.5 +/- 6.0 nmol/L, respectively); increased cardiac MDA (0.56 +/- 0.03 vs 0.94+/-0.07 nmol/mg protein) and PBMC H2O2 production (63.5 +/- 7.5 vs 154.0 +/- 25.2 mcb) and reduced (P < 0.05) plasma alpha1-AP activity (39.8 +/- 0.6 vs 29.6 +/- 1.8 mM), each prevented by Cina (0.66 +/- 0.04 mmol/mg protein, 58.2 +/- 12.7 mcb and 37.0 +/- 1.2 mM, respectively).

PTH-mediated intracellular Ca2+ overloading accounts for the induction of oxidative stress in diverse tissues in rats with aldosteronism and which can be prevented by Cina.