Pharmacological properties of the calcimimetic compound NPS R-568 in vitro and in vivo

被引：1

作者：

Murakami Y. ^{[1
]}

Furuya Y. ^{[2
]}

Wada M. ^{[2
]}

Sakai T. ^{[1
]}

Nagano N. ^{[2
]}

机构：

[1] Pharmaceutical Research Laboratory, Gunma, Kirin Brewery

[2] Pharmaceutical Development Laboratory, Takasaki, Gunma 370-1295, Kirin Brewery

来源：

Clinical and Experimental Nephrology | 2000年 / 4卷 / 4期

关键词：

Calcimimetics; Calcium receptor; HEK293; Intracellular Ca[!sup]2+[!/sup; NPS R-568;

D O I：

10.1007/s101570070004

中图分类号：

学科分类号：

摘要：

Background. The Ca2+ receptor (CaR) plays a key role in maintaining Ca2+ homeostasis by its presence in the parathyroid gland and kidney. NPS R-568 (referred to as KRN568 in Japan) is a phenylalkylamine compound that activates the CaR. It has been difficult to study Ca2+-sensing mechanisms because of the lack of cell model systems that express reasonable numbers of CaR coupled to downstream effectors and physiological responses. This study was conducted to evaluate the effects of NPS R-568 on the CaR both in vitro and in vivo. Methods. Western blotting analysis of CaR was performed to confirm the existence of CaR in human embryonic kidney 293 (HEK293) cells expressing human CaR (HuCaR-HEK293). Intracellular Ca2+ concentration ([Ca2+]i) and inositol trisphosphate (IP3) content were measured in HuCaR-HEK293 after the addition of NPS R-568 and other agonists. Male Sprague-Dawley rats received NPS R-568 orally, and plasma Ca2+ levels and serum parathyroid hormone (PTH) levels were determined. Results. Western blotting analysis of the crude plasma membrane fraction prepared from HuCaR-HEK293 identified bands immunoreactive with a human CaR-specific antibody. NPS R-568 dose-dependently and stereoselectively increased [Ca2+]i in HuCaR-HEK293, whereas NPS R-568 had no effects in wild-type HEK293 cells. These effects of NPS R-568 were associated with an increase in cytoplasmic IP3 levels and were abolished in the absence of extracellular Ca2+. Single oral administration of NPS R-568 suppressed PTH secretion, followed by decreased plasma Ca2+ levels, in normal rats. Conclusions. These results suggest that NPS R-568 activates CaR and suppresses PTH secretion in vitro and in vivo.

引用

页码：293 / 299

页数：6

共 24 条

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