Padi Satyanarayana S V, Chopra Kanwaljit
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Nephron. 2002;92(3):685-92. doi: 10.1159/000064095.
BACKGROUND: Cyclosporine A (CsA) is the first-line immunosuppressant employed for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA nephrotoxicity. The present study was designed to investigate effects of carvedilol, a third-generation beta-blocker with potent free radical-scavenging activity on CsA-induced oxidative stress and resultant renal dysfunction in a rat model of chronic CsA nephrotoxicity. METHODS: Carvedilol (2.0 and 4.0 mg/kg i.p.) and propranolol (10 mg/kg i.p.) were administered to separate group of animals 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Tissue lipid peroxidation was measured as thiobarbituric acid-reacting substances (TBARS). Renal morphological alterations were assessed by histopathological examination of hematoxylin-eosin, PAS and Masson's trichrome stained sections of the kidneys. RESULTS: CsA (20 mg/kg s.c) administration for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Propranolol neither decreased TBARS nor improved the renal dysfunction and morphological changes induced by CsA. Both doses of carvedilol markedly reduced elevated levels of TBARS, whereas the higher dose of carvedilol significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. CONCLUSIONS: These data clearly indicate the renoprotective potential of carvedilol in CsA-induced nephrotoxicity and suggest a significant contribution of its antilipoperoxidative property in this beneficial effect.
背景：环孢素A（CsA）是用于实体器官移植和自身免疫性疾病治疗的一线免疫抑制剂。肾毒性是CsA使用的主要限制因素。最近的证据表明，活性氧（ROS）在介导CsA肾毒性中起重要作用。本研究旨在探讨卡维地洛（一种具有强大自由基清除活性的第三代β受体阻滞剂）对慢性CsA肾毒性大鼠模型中CsA诱导的氧化应激及由此导致的肾功能障碍的影响。 方法：将卡维地洛（2.0和4.0mg/kg腹腔注射）和普萘洛尔（10mg/kg腹腔注射）分别在CsA（20mg/kg皮下注射）给药前24小时及给药期间同时给予不同组动物，持续21天。通过估算血浆肌酐、血尿素氮（BUN）、肌酐和尿素清除率来评估肾功能。以硫代巴比妥酸反应物质（TBARS）衡量组织脂质过氧化。通过对苏木精-伊红、PAS和Masson三色染色的肾脏切片进行组织病理学检查来评估肾脏形态学改变。 结果：与溶剂处理的大鼠相比，皮下注射20mg/kg CsA 21天导致TBARS水平升高，肾功能恶化，表现为血浆肌酐、BUN升高，肌酐和尿素清除率降低。CsA处理的大鼠肾脏显示严重的条纹状间质纤维化、小动脉病变、肾小球基底膜增厚、肾小管空泡化和透明管型。普萘洛尔既未降低TBARS，也未改善CsA诱导的肾功能障碍和形态学变化。两种剂量的卡维地洛均显著降低了升高的TBARS水平，而较高剂量的卡维地洛显著减轻了CsA处理大鼠的肾功能障碍和形态学变化。 结论：这些数据清楚地表明卡维地洛对CsA诱导的肾毒性具有肾脏保护潜力，并提示其抗脂质过氧化特性在这一有益作用中起重要作用。
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