title: Selective ET(A) receptor blockade protects against cisplatin-induced acute renal failure in male rats.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Azarita, PO Box 21521, Alexandria, Egypt. Electronic address: meeshoo7@hotmail.com.
authors.forename: Mai M
authors.initials: MM
authors.lastname: Helmy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
authors.forename: Maged W
authors.initials: MW
authors.lastname: Helmy
authors.affiliation: Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Azarita, Alexandria, Egypt.
authors.forename: Dina M
authors.initials: DM
authors.lastname: Abd Allah
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
authors.forename: Ahmad M
authors.initials: AM
authors.lastname: Abo Zaid
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Azarita, PO Box 21521, Alexandria, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Mohy El-Din
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D002945:Cisplatin
keywords: BQ-123; Cisplatin; ET(A) receptors; Endothelin-1; Nephrotoxicity; SOD