Helmy Mai M, Helmy Maged W, Abd Allah Dina M, Abo Zaid Ahmad M, Mohy El-Din Mahmoud M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Azarita, PO Box 21521, Alexandria, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
Eur J Pharmacol. 2014 May 5;730:133-9. doi: 10.1016/j.ejphar.2014.03.002. Epub 2014 Mar 14.
The present study aims to investigate the possibility that inhibiting the physiological function of endothelin-1 (ET-1) by blocking its receptors would significantly decrease the nephrotoxic effect of cisplatin. Therefore the study was designed to investigate the effect of treatment with BQ-123, the selective endothelin receptor-A (ET(A)) blocker, and bosentan, the non-selective endothelin receptor blocker, on the cisplatin-induced structural, functional, and biochemical alterations in the rat kidney. Rats were divided into four groups: control (given a single dose of normal saline, i.p.), cisplatin (given a single dose of cisplatin, 6mg/kg, i.p.), cisplatin+BQ-123 (1mg/kg, i.p.), and cisplatin+bosentan (30mg/kg, orally via gavage). Each of the two blockers was administered in two doses; 1h before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in blood urea nitrogen and serum creatinine concentrations at 96h following cisplatin injection. Increased concentrations of malondialdehyde, tumor necrosis factor-α (TNF-α) and caspase-3, decreased nitric oxide (NO) production and superoxide dismutase (SOD) activity in kidney homogenates were observed at 96h following cisplatin injection, in addition to a typical 'acute tubular necrosis' pattern. BQ-123 ameliorated the structural and functional injuries caused by cisplatin mainly via restoring SOD activity, in addition to other antioxidant parameters, NO, TNF-α and caspase-3 concentrations. This study further proves that ET(A) but not ETB receptors are involved in cisplatin-induced nephrotoxicity. The selective ET(A) antagonist BQ-123 ameliorated the cisplatin-induced deleterious effects and showed reno-protective effect against cisplatin-induced acute renal damage.
本研究旨在探讨通过阻断内皮素-1（ET-1）受体来抑制其生理功能是否会显著降低顺铂的肾毒性作用。因此，本研究旨在探讨选择性内皮素A受体（ET(A)）阻滞剂BQ-123和非选择性内皮素受体阻滞剂波生坦对顺铂诱导的大鼠肾脏结构、功能和生化改变的影响。将大鼠分为四组：对照组（腹腔注射单剂量生理盐水）、顺铂组（腹腔注射单剂量顺铂，6mg/kg）、顺铂+BQ-123组（腹腔注射1mg/kg BQ-123）和顺铂+波生坦组（经口灌胃给予30mg/kg波生坦）。两种阻滞剂均分两次给药，在顺铂给药前1小时和给药后一天各给药一次。急性给予顺铂后，在注射顺铂96小时时，血尿素氮和血清肌酐浓度显著升高。在注射顺铂96小时时，除了典型的“急性肾小管坏死”模式外，还观察到肾匀浆中丙二醛、肿瘤坏死因子-α（TNF-α）和半胱天冬酶-3浓度升高，一氧化氮（NO）生成减少和超氧化物歧化酶（SOD）活性降低。BQ-123主要通过恢复SOD活性以及其他抗氧化参数、NO、TNF-α和半胱天冬酶-3浓度，改善了顺铂引起的结构和功能损伤。本研究进一步证明，参与顺铂诱导的肾毒性的是ET(A)受体而非ETB受体。选择性ET(A)拮抗剂BQ-123改善了顺铂诱导的有害作用，并对顺铂诱导的急性肾损伤显示出肾脏保护作用。
