The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor

J Clin Invest. 1997 Dec 15;100(12):2977-83. doi: 10.1172/JCI119851.

Abstract

Parathyroid (PT) cell hyperplasia is a common consequence of chronic renal insufficiency (CRI). NPS R-568 is a phenylalkylamine compound that acts as an agonist (calcimimetic) at the cell surface calcium receptor (CaR). To test the hypothesis that the CaR plays a role in PT hyperplasia in CRI, we tested the effect of NPS R-568 on PT cell proliferation in rats with renal insufficiency. Rats were subjected to 5/6 nephrectomy and then infused intraperitoneally with 5-bromodeoxyuridine (BrdU) to label S-phase cells. Two groups of nephrectomized rats received NPS R-568 by gavage twice daily for 4 d (1.5 and 15 mg/kg body wt). On day 5, the number of BrdU-positive PT cells of vehicle-treated nephrectomized rats was 2.6-fold greater than that of the sham-operated control. Low and high doses of NPS R-568 reduced the number of BrdU-positive PT cells by 20 and 50%, respectively. No changes in staining, however, were observed in ileal epithelial cells (CaR-negative) or in thyroidal C-cells (CaR-positive). Furthermore, the effect of NPS R-568 could not be explained by changes in serum 1,25(OH)2D3 or phosphorus. These results indicate that NPS R-568 suppresses PT cell proliferation in rats with renal insufficiency, and lend support to the linkage between the CaR and PT hyperplasia in CRI.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Apoptosis
  • Blood Urea Nitrogen
  • Body Weight / drug effects
  • Calcitriol / metabolism
  • Calcium / agonists*
  • Calcium / metabolism
  • Cell Division / drug effects
  • Creatinine / metabolism
  • Disease Models, Animal
  • Growth Inhibitors / pharmacology*
  • Male
  • Parathyroid Glands / drug effects*
  • Parathyroid Glands / pathology
  • Parathyroid Hormone / metabolism
  • Phenethylamines
  • Propylamines
  • Rats
  • Rats, Sprague-Dawley
  • Renal Insufficiency / metabolism
  • Renal Insufficiency / pathology*

Substances

  • Aniline Compounds
  • Growth Inhibitors
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • Parathyroid Hormone
  • Phenethylamines
  • Propylamines
  • Creatinine
  • Calcitriol
  • Calcium