Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism

Background. Secondary hyperparathyroidism (secondary HPT) in chronic renal insufficiency (CRI) is characterized by multiglandular hyperplasia. Methods. In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus load ing. Six days after surgery, high-phosphorus diet feeding was started, and NPS R-568 was administered to the rats for 56 days either by daily gavage ( 30 or 100 mu mol/kg) or by continuous subcutaneous infusion (20 mu mol/kg d ay). Results. After 54 days, serum PTH levels in vehicle-treated CRI rats were 1 019 vs. 104 pg/mL in sham-operated controls. Infusion of NPS R-568 maintain ed serum PTH at levels comparable with those of sham-operated controls, whe reas daily gavage also prevented much of the increase in CRI controls and d ecreased PTH levels intermittently in a dose-dependent fashion. Parathyroid gland enlargement was caused predominantly by hyperplasia. Total cell numb er per kg body wt was 3.5-fold higher in vehicle-treated CRI rats than in s ham-operated controls. Both infusion and high-dose gavage of NPS R-568 comp letely prevented the increase in parathyroid cell number. Conclusion. These results demonstrate that the calcimimetic compound NPS R- 568 can prevent both the increase in serum PTH levels and parathyroid hyper plasia in rats with CRI and severe secondary HPT. Moreover, these changes o ccurred despite decreases in serum 1,25(OH)(2)D-3, and increases in serum p hosphate, suggesting a dominant role for the calcium receptor in regulating parathyroid cell proliferation.