ROLE OF NITRERGIC AND ENDOTHELIN PATHWAYS MODULATIONS IN CISPLATIN-INDUCED NEPHROTOXICITY IN MALE RATS

Although the protective role of either nitric oxide (NO) or endothelin (ET) receptors modulation on the severity of cisplatin-induced nephrotoxicity has been recognized in previous studies including our own, the possible interaction between the two pathways remains obscure. In this study, we tested for the first time the possible interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats. Sprague Dawley male rats were divided into four groups: control (given a single dose of normal saline, i.p.), cisplatin (6 mg/kg, i.p.), cisplatin + sildenafil (2 mg/kg, i.p.), cisplatin + sildenafil + BQ-123 (1 mg/kg, i.p.). Each of the co-administered drugs was given in two doses; one hour before and one day after the cisplatin dose. Acute cisplatin administration resulted in significant increases in blood urea nitrogen (BUN) and serum creatinine levels at 96 hours following cisplatin injection. Increased levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha) and caspase-3, decreased nitrite/nitrate level and superoxide dismutase (SOD) activity in kidney homogenates were also observed following cisplatin injection, in addition to a typical 'acute tubular necrosis' pattern. According to the obtained results, the co-adminstration of sildenafil alone with cisplatin offered a reno-protective effect comparable to that obtained following the concurrent administration of both sildenafil and the selective ET-A receptor antagonist BQ-123. Thus, the current study is the first to reveal that the presence of an intact NO/cGMP system may offer a moderate reno-protective effect against cisplatin-induced nephrotoxicity even in the presence of ET-A-mediated vasoconstriction, suggesting the absence of obvious functional interaction between the nitrergic and endothelin pathways in cisplatin-induced nephrotoxicity in male rats.