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NPS R-568 is a Ca2+ receptor agonist ("calcimimetic") compound that reduces circulating parathyroid hormone (PTH) levels in rats and humans with mild secondary hyperparathyroidism (secondary HPT) resulting from chronic renal insufficiency (CRI). These studies extend those observations to show that NPS R-568 is equally effective in decreasing plasma PTH and Ca2+ levels in rats with mild or severe secondary HPT, resulting either from CRI or from dietary calcium deficiency. Male rats were 5/6 nephrectomized and fed either normal chow or a high-phosphorus diet; other normal rats were fed a low-calcium diet. When secondary HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h. PTH levels decreased to a minimum level within 30 min in both CRI and calcium deficiency models of secondary HPT. PTH and Ca2+ levels remained significantly depressed for >3 h after dosing. The percentage decrease in PTH levels was unaffected by the severity of secondary HPT or the basal plasma Ca2+ or phosphate levels. In rats with severe secondary HPT, the minimum plasma PTH level after NPS R-568 was greater than the basal level in mild secondary HPT. Thus, NPS R-568 is equally effective in suppressing plasma PTH and Ca2+ levels in rats with mild or severe renal or nutritional secondary HPT.

Extracellular ionized calcium (Ca(2+)) is the primary physiological regulator of parathyroid hormone (PTH) secretion and the G protein-coupled receptor (CaR) that mediates this response has been cloned from bovine and human parathyroid glands. The Ca(2+) set-point for the regulation of PTH secretion is right-shifted in primary hyperparathyroidism (1°HPT), but whether there is a similar shift in 2°HPT is unclear. Additionally, the molecular defects associated with such changes in the set-point remain uncharacterized. These experiments were designed to determine (1) if changes in set-point occur in rats with 2°HPT induced by chronic renal insufficiency (CRI) or dietary Ca deficiency, and (2) whether any changes in set-point are mirrored by changes in steady-state mRNA levels for the parathyroid CaR. CaR mRNA levels were quantified in pairs of glands from individual rats using a solution hybridization assay. Blood urea nitrogen and PTH levels were ∼ 4-fold higher in rats with CRI induced by 5/6 nephrectomy 7 weeks earlier. Rats with CRI were also significantly hypocalcemic and hyperphosphatemic. The setpoint was unchanged in CRI rats and CaR mRNA levels were also unaffected. Normal rats fed a 0.02% Ca diet for 6 weeks were markedly hypocalcemic, and had 10- and 15-fold increases in plasma PTH and 1,25-dihydroxyvitamin D(3) levels, respectively. Technical problems prevented assessment of the set-point in these animals, but parathyroid gland CaR mRNA levels were identical in both dietary groups. Thus, neither alterations in mRNA levels for the CaR nor changes in the set-point play demonstrable roles in the pathogenesis of 2°HPT in these models.