The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.
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.
Wada
M
M
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Takasaki-shi, Gunma 370-12, Japan.
Furuya
Y
Y
Sakiyama
J
J
Kobayashi
N
N
Miyata
S
S
Ishii
H
H
Nagano
N
N
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000819:agonists* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D006131:Growth Inhibitors / Q000494:pharmacology*; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects* / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism / Q000473:pathology*
D000814:Aniline Compounds; D006131:Growth Inhibitors; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium