Department of Pharmacology and Toxicology, Faculties of Pharmacy, University of Cairo, Cairo, Egypt.
Chemotherapy. 2009;55(6):399-406. doi: 10.1159/000262453. Epub 2009 Nov 30.
In the present study, we investigated the possible modulatory effect of losartan, an angiotensin receptor blocker, on oxidative stress induced by cisplatin (CDDP) as well as on CDDP uptake by the kidney.
Rats were injected with a single dose of CDDP (7 mg/kg) and/or losartan (in either a single dose of 60 mg/kg or divided doses (10 mg/kg daily for 6 days), starting 1 h before CDDP injection. In addition, rat renal cortical slices were incubated with CDDP (2 mM) and/or losartan (2 mM) for 4 h. Nephrotoxicity was evaluated by measuring serum creatinine and blood urea nitrogen (BUN) in vivo and lactate dehydrogenase (LDH) leakage in vitro; histopathological examination of kidney tissue was also done. Oxidative stress markers including reduced glutathione (GSH) and lipid peroxides were also assessed. Furthermore, CDDP uptake by renal cortical slices was determined.
Losartan has protective effects against CDDP-induced nephrotoxicity as evidenced by restoration of normal serum levels of creatinine and BUN, and LDH leakage. Histopathological examination of the kidney confirmed these results. Also, losartan significantly counteracted CDDP-induced lipid peroxidation and GSH depletion. However, losartan did not affect CDDP uptake by the kidney.
Our results indicate that losartan has proved to be a promising drug for clinical use as a nephroprotectant against CDDP-induced nephrotoxicity.
在本研究中，我们研究了血管紧张素受体阻滞剂氯沙坦对顺铂（CDDP）诱导的氧化应激以及对肾脏摄取 CDDP 的可能调节作用。
大鼠单次注射 CDDP（7mg/kg）和/或氯沙坦（单次剂量 60mg/kg 或分剂量（10mg/kg，每日一次，共 6 天），在注射 CDDP 前 1 小时开始。此外，将大鼠肾皮质切片与 CDDP（2mM）和/或氯沙坦（2mM）孵育 4 小时。体内通过测量血清肌酐和血尿素氮（BUN）以及体外通过乳酸脱氢酶（LDH）渗漏来评估肾毒性；还对肾组织进行了组织病理学检查。还评估了氧化应激标志物，包括还原型谷胱甘肽（GSH）和脂质过氧化物。此外，还测定了肾皮质切片对 CDDP 的摄取。
氯沙坦对 CDDP 诱导的肾毒性具有保护作用，表现为恢复正常的血清肌酐和 BUN 水平以及 LDH 渗漏。肾组织学检查证实了这些结果。此外，氯沙坦显著拮抗 CDDP 诱导的脂质过氧化和 GSH 耗竭。然而，氯沙坦不影响 CDDP 被肾脏摄取。
我们的结果表明，氯沙坦已被证明是一种有前途的药物，可用于临床，作为一种肾保护剂，预防 CDDP 诱导的肾毒性。
