Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats
Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats
复制标题
DOI：
10.1016/j.tox.2006.11.067
复制
发表时间：
2007-02-28
期刊：
影响因子：
4.5
通讯作者：
Shao, Lang
中科院分区：
文献类型：
--
作者：
Liu, Li-Lin;Li, Qi-Xiong;Shao, Lang
本研究的目的是通过生化、组织病理学和免疫组织化学方法比较二氢吡啶类钙拮抗剂硝苯地平、尼群地平、氨氯地平对阿霉素 (DXR) 诱导的大鼠肾毒性的作用。雄性Sprague-Dawley大鼠被随机分为5个实验组：对照组； DXR； DXR + 硝苯地平（15 毫克/千克）； DXR+尼群地平（10mg/kg）； DXR+氨氯地平（5毫克/千克）。结果显示，单独使用 DXR 治疗会引起尿蛋白、血清肌酐 (SCr) 和血尿素氮 (BUN) 水平的显着变化。与氨氯地平联合给药有效逆转了 DXR 对这些参数的影响。相比之下，硝苯地平和尼群地平要么没有作用，要么加剧了 DXR 引起的尿蛋白、SCr 和 BUN 水平的变化。此外，DXR治疗导致丙二醛（MDA）、一氧化氮（NO）、一氧化氮合酶（NOS）水平显着升高，还原型谷胱甘肽（GSH）、谷胱甘肽-S-转移酶（GST）和超氧化物歧化酶（SOD）水平显着降低。与氨氯地平合用可显着降低这些影响，但硝苯地平不受影响，尼群地平则加剧这些影响。除了生化变化之外，组织病理学研究还表明 DXR 会导致肾脏出现显着的结构损伤。在所有接受 DXR 治疗的大鼠中均观察到肾小球细胞凋亡、Bcl-2 表达减少和 Bax 表达增加。与氨氯地平合用可有效逆转 DXR 的作用，而硝苯地平和尼群地平则没有效果。总之，这项研究清楚地表明氨氯地平可以预防 DXR 诱导的肾毒性，而硝苯地平和尼群地平则没有作用。 (c) 2006 Elsevier Ireland Ltd. 保留所有权利。
The aim of this study was to compare the roles of dihydropyridine calcium antagonists nifedipine, nitrendipine, amlodipilne on doxorubicin (DXR)-induced nephrotoxicity in rats using biochemical, histopathological and immunohistochemical approaches. Male Sprague-Dawley rats were randomly divided into five experimental groups: control; DXR; DXR + nifedipine (15 mg/kg); DXR+ nitrendipine (10mg/kg); DXR+amlodipine (5 mg/kg). Results showed that treatment with DXR alone caused significant changes in the levels of urinary protein, serum creatinine (SCr), and blood urea nitrogen (BUN). Co-administration with amlodipine effectively reversed the effect of DXR on these parameters. In contrast, nifedipine and nitrendipine either had no effect or worsened DXR induced changes in the levels of urinary protein, SCr and BUN. Furthermore, DXR treatment caused significant increases in the levels of malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) and significant decreases in the levels of reduced glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD). These effects were significantly reduced by co-administration with amlodipine but not affected by nifedipine and worsened by nitrendipine. In addition to the biochemical changes, histopathological studies showed that DXR caused significant structural damages in the kidneys. Glomerular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with DXR. Co-administration with amlodipine effectively reversed the effect of DXR while nifedipine and nitrendipine had no effect. In conclusion, this study clearly indicated that amlodipine protected against DXR-induced nephrotoxicity while nifedipine and nitrendipine had no effect. (c) 2006 Elsevier Ireland Ltd. All rights reserved.