Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats.
The secondary hyperparathyroidism that develops in rats with chronic renal insufficiency (CRI) can be totally prevented by activation of the parathyroid Ca(2+) receptor with a calcimimetic compound, when treatment is initiated before parathyroid cell hyperplasia and increased circulating parathyroid hormone levels develop. In clinical practice, however, secondary hyperparathyroidism is usually manifest by the time CRI is diagnosed. This study examined the effects of daily oral gavage or continuous subcutaneous infusion for 8 wk of the calcimimetic NPS R-568 on the progression of established mild or moderate-to-severe secondary hyperparathyroidism in rats with CRI induced by 5/6 nephrectomy. Both oral and infused NPS R-568 completely prevented further hyperplasia but did not reduce total parathyroid cell number below that present at the initiation of treatment. This prevention of cellular proliferation occurred despite increases in plasma phosphate and decreases in Ca(2+) and 1, 25-dihydroxyvitamin D levels, and supports the view that the Ca(2+) receptor is the dominant regulator of parathyroid cell hyperplasia in addition to parathyroid hormone secretion. The clinical implications of these findings suggest that controlling Ca(2+) receptor activity with calcimimetic compounds could be sufficient to manage secondary hyperparathyroidism in CRI.
Chin
J I
JI
NPS Pharmaceuticals, Inc., Salt Lake City, Utah.
Miller
Scott C
SC
NPS Pharmaceuticals, Inc., Salt Lake City, Utah.
Wada
Michihito
M
Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Takasaki-shi, Gunma, Japan.
Nagano
Nobuo
N
Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Takasaki-shi, Gunma, Japan.
Nemeth
Edward F
EF
NPS Pharmaceuticals, Inc., Salt Lake City, Utah.
Fox
John
J
NPS Pharmaceuticals, Inc., Salt Lake City, Utah.
D000704:Analysis of Variance; D000814:Aniline Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001806:Blood Urea Nitrogen; D002118:Calcium / Q000819:agonists* / Q000097:blood; D002135:Calcium-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006965:Hyperplasia; D010280:Parathyroid Glands / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010627:Phenethylamines; D010710:Phosphates / Q000097:blood; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000097:blood; D014511:Uremia / Q000150:complications*
D000814:Aniline Compounds; D002135:Calcium-Binding Proteins; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D010710:Phosphates; D011437:Propylamines; D003404:Creatinine; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D002118:Calcium