Sodam B R, Awumey E M, Sampson W H, Epstein S
Division of Endocrinology, Department of Medicine, MCP-Hahnemann University, Philadelphia, Pennsylvania, USA.
Calcif Tissue Int. 2001 Feb;68(2):117-21. doi: 10.1007/BF02678150.
Cyclosporine A (CsA) is a potent immunosuppressive agent widely used to prevent allograft rejection. In vivo administration of CsA is associated with the development of high-turnover osteopenia. Endothelin-1 (ET), a vasoconstrictive peptide, has been implicated in CsA-induced nephrotoxicity and hypertension. Recent evidence suggests that endothelin plays a pivotal role in bone metabolism. The present study was designed to investigate whether L-754,142 (ETRA), the combined endothelin A and B receptor antagonist, when given to rats, would favorably modify the bone loss caused by CsA. Fifty, 5-month-old male Sprague-Dawley rats were randomly divided into five groups of 10 rats each. The first group served as a basal control. The remaining four groups received, by daily gavage for 28 days, (1) a combined CsA and ETRA vehicle, (2) CsA, 10 mg/kg, (3) ETRA, 30 mg/kg, and (4) CsA, 10 mg/kg and ETRA, 30 mg/kg, respectively. Rats were weighed and venous blood was collected on days 0, 14, 28 for determination of BUN, creatinine, calcium, PTH, osteocalcin, and 1,25(OH)2 D. Tibiae, after double labeling, were removed following sacrifice for histomorphometry. Both CsA-treated rats and CsA/ETRA-treated rats demonstrated trabecular osteopenia with raised serum osteocalcin, and 1,25(OH)2D levels when compared to control animals (P < 0.05). Rats given CsA alone developed renal impairment, as shown by an increased BUN. The combination group did not develop renal impairment. The results suggest that endothelin may contribute to the development of CsA-induced nephrotoxicity, which was prevented by ETRA, but does not seem to play a role in CsA-induced osteopenia.
环孢素A（CsA）是一种强效免疫抑制剂，广泛用于预防同种异体移植排斥反应。体内给予CsA与高转换型骨质减少的发生有关。内皮素-1（ET）是一种血管收缩肽，与CsA诱导的肾毒性和高血压有关。最近的证据表明内皮素在骨代谢中起关键作用。本研究旨在调查给予大鼠内皮素A和B受体联合拮抗剂L-754,142（ETRA）是否会有利地改善由CsA引起的骨质流失。50只5月龄雄性Sprague-Dawley大鼠随机分为五组，每组10只。第一组作为基础对照组。其余四组通过每日灌胃28天，分别给予：（1）CsA和ETRA的赋形剂；（2）10mg/kg的CsA；（3）30mg/kg的ETRA；（4）10mg/kg的CsA和30mg/kg的ETRA。在第0、14、28天对大鼠称重并采集静脉血，用于测定血尿素氮、肌酐、钙、甲状旁腺激素、骨钙素和1,25(OH)2D。处死大鼠后取出经双重标记的胫骨进行组织形态计量学分析。与对照动物相比，CsA处理组大鼠和CsA/ETRA处理组大鼠均表现出小梁骨减少，血清骨钙素和1,25(OH)2D水平升高（P<0.05）。单独给予CsA的大鼠出现肾功能损害，表现为血尿素氮升高。联合用药组未出现肾功能损害。结果表明，内皮素可能促成CsA诱导的肾毒性的发生，ETRA可预防这种肾毒性，但内皮素似乎在CsA诱导的骨质减少中不起作用。
