拟钙剂NPS R-467对幼鼠速尿诱导的肾钙质沉着症的影响。

Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat.

作者信息

Pattaragarn Anirut, Fox John, Alon Uri S

机构信息

Section of Pediatric Nephrology, Children's Mercy Hospital, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.

出版信息

Kidney Int. 2004 May;65(5):1684-9. doi: 10.1111/j.1523-1755.2004.00564.x.

DOI:10.1111/j.1523-1755.2004.00564.x

PMID:15086907

Abstract

BACKGROUND

Furosemide induces nephrocalcinosis in both humans and animals. We showed previously that parathyroidectomy protected against the development of furosemide-induced nephrocalcinosis in young rats, indicating a possible role for parathyroid hormone (PTH) in its pathogenesis. Calcimimetic agents such as NPS R-467 are potent and selective agonists at the calcium-sensing receptor in parathyroid glands and inhibit PTH secretion.

METHODS

To determine whether NPS R-467 could, like parathyroidectomy, prevent furosemide-induced nephrocalcinosis, we studied 35 6-week-old male Sprague-Dawley rats, divided into five groups. Group A served as control, group B received intraperitoneally furosemide (40 mg/kg), groups C, D, and E received furosemide and NPS R-467 intraperitoneally at doses of 10, 20, and 40 micromol/kg, respectively, daily for 8 days. During the last 3 days, animals were placed in metabolic cages for measurement of urine output, food, and water intake. Blood and kidneys were collected on day 8, 60 to 90 minutes after the last doses. Kidney calcium content was measured and nephrocalcinosis scoring (0 to 5) was assessed histologically.

RESULTS

Furosemide increased urine output and fluid intake, and decreased body weight gain similarly in all groups. Serum PTH levels (mean +/- SD) were significantly higher in furosemide-treated control animals (276 +/- 226 pg/mL vs. 64 +/- 21 pg/mL); NPS R-467 induced a dose-dependent decrease in PTH levels (52 +/- 51 pg/mL, 18 +/- 7 pg/mL, and 13 +/- 3 pg/mL in groups C, D, and E, respectively). Plasma Ca(2+) was slightly, but significantly lower in all three NPS R-467 treated groups (5.1 +/- 0.4 mg/dL, 4.8 +/- 0.3 mg/dL, and 4.5 +/- 0.3 mg/dL in groups C, D, and E, respectively) compared to 5.7 +/- 0.1 mg/dL and 5.5 +/- 0.2 mg/dL in groups A and B, respectively. Furosemide treatment induced a substantial increase in kidney calcium content (1819 +/- 664 microg/g dry weight vs. 126 +/- 26 microg/g dry weight) and nephrocalcinosis scoring (5.0 +/- 0.0 vs. 0.0 +/- 0.0). Treatment with NPS R-467 ameliorated the furosemide-induced increase in kidney calcium content (673 +/- 312 microg/g, 361 +/- 188 microg/g, and 563 +/- 291 microg/g) and nephrocalcinosis scoring (2.2 +/- 1.2, 0.7 +/- 0.8, and 1.0 +/- 1.2) in groups C, D, and E, respectively.

CONCLUSION

The calcimimetic agent NPS R-467 prevents the development of hyperparathyroidism and attenuates nephrocalcinosis in the furosemide-treated young rat.

摘要

背景

呋塞米可在人类和动物中诱发肾钙质沉着症。我们之前的研究表明，甲状旁腺切除术可预防幼鼠发生呋塞米诱导的肾钙质沉着症，提示甲状旁腺激素（PTH）在其发病机制中可能发挥作用。诸如NPS R - 467等拟钙剂是甲状旁腺中钙敏感受体的强效选择性激动剂，可抑制PTH分泌。

方法

为确定NPS R - 467是否能像甲状旁腺切除术一样预防呋塞米诱导的肾钙质沉着症，我们对35只6周龄雄性Sprague - Dawley大鼠进行了研究，将其分为五组。A组作为对照组，B组腹腔注射呋塞米（40 mg/kg），C、D、E组分别腹腔注射剂量为10、20和40 μmol/kg的呋塞米和NPS R - 467，每日一次，共8天。在最后3天，将动物置于代谢笼中以测量尿量、食物和水的摄入量。在最后一次给药后60至90分钟的第8天采集血液和肾脏。测量肾脏钙含量并通过组织学评估肾钙质沉着症评分（0至5分）。

结果

呋塞米使所有组的尿量和液体摄入量增加，体重增加减少。呋塞米治疗的对照动物血清PTH水平（均值±标准差）显著更高（276±226 pg/mL对64±21 pg/mL）；NPS R - 467使PTH水平呈剂量依赖性降低（C、D、E组分别为52±51 pg/mL、18±7 pg/mL和13±3 pg/mL）。与A组的5.7±0.1 mg/dL和B组的5.5±0.2 mg/dL相比，所有三个NPS R - 467治疗组的血浆Ca(2+)均略有但显著降低（C、D、E组分别为5.1±0.4 mg/dL、4.8±0.3 mg/dL和4.5±0.3 mg/dL）。呋塞米治疗导致肾脏钙含量大幅增加（1819±664 μg/g干重对126±26 μg/g干重）和肾钙质沉着症评分增加（5.0±0.0对0.0±0.0）。NPS R - 467治疗分别改善了C、D、E组中呋塞米诱导的肾脏钙含量增加（673±312 μg/g、361±188 μg/g和563±291 μg/g）和肾钙质沉着症评分（2.2±1.2、0.7±0.8和1.0±1.2）。