The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands.
We previously demonstrated that extracellular calcium regulates vitamin D receptor (VDR) expression by parathyroid cells. Since the calcimimetic R-568 potentiates the effects of calcium on the calcium-sensing receptor, it was hypothesized that administration of R-568 may result in increased VDR expression in parathyroid tissue. In vitro studies of the effect of R-568 on VDR mRNA and protein were conducted in cultures of whole rat parathyroid glands and human hyperplastic parathyroid glands. In vivo studies in Wistar rats examined the effect of R-568 and calcitriol alone and in combination. Incubation of rat parathyroid glands in vitro with R-568 (0.001-1 microM) resulted in a dose-dependent decrease in parathyroid hormone (PTH) secretion and an increase in VDR expression (mean +/- SE). Incubation in 1 mM calcium + 0.001 microM R-568 elicited an increase in VDR mRNA (306 +/- 46%) similar to the maximum increase detected with 1.5 mM calcium (330 +/- 42%). In vivo, VDR mRNA was increased after administration of R-568 (168 +/- 9%, P < 0.001 vs. control) or calcitriol (198 +/- 16%, P < 0.001 vs. control). Treatment with R-568 also increased VDR protein in normal rat parathyroid glands and in human parathyroid glands with diffuse, but not nodular, hyperplasia. In conclusion, the present study shows that the calcimimetic R-568 exerts a stimulatory effect on VDR expression in the parathyroid glands of study models and provides additional evidence for the use of calcimimetics in the treatment of secondary hyperparathyroidism.
Rodriguez
M E
ME
Unidad de Investigacion, Servicio de Nefrologia, Hospital Universitario Reina Sofia, Cordoba, Spain.
Almaden
Y
Y
Cañadillas
S
S
Canalejo
A
A
Siendones
E
E
Lopez
I
I
Aguilera-Tejero
E
E
Martin
D
D
Rodriguez
M
M
D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000819:agonists* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D006961:Hyperparathyroidism / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D066298:In Vitro Techniques; D008297:Male; D010280:Parathyroid Glands / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*
D000814:Aniline Compounds; D004338:Drug Combinations; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium