Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine
Background. Nitric oxide (NO) concentration in serum is altered by cisplatin (CP), and NO influences CP-induced nephrotoxicity. The effect of nephroprotectant agent supplementation (vitamin E, human recombinant erythropoietin (EPO), or n-acetylcysteine (NAC)) on the NO metabolites levels after CP administration in the two genders was determined. Methods. Sixty-four adult Wistar rats were randomly divided into 10 groups. Male and female rats in different groups received vehicle (saline), CP (7？mg/kg) alone, CP plus EPO (100？IU/kg), CP plus vitamin E (250？mg/kg), and CP plus NAC (600？mg/kg). CP was administrated as a single dose, but the supplementations were given for a period of 7 days. Results. In male rats, the serum levels of total NO metabolites (NOx) and nitrite were increased significantly ( ) by CP. However, vitamin E significantly reduced the serum levels of these metabolites, which was increased by administration of CP ( ), and such findings were not observed for female rats. The EPO or NAC did not influence NO metabolites neither in male rats nor in female rats. Conclusion. Although vitamin E, EPO, and NAC are reported to be nephroprotectant agents against CP-induced nephrotoxicity, only vitamin E could reduce the level of all NO metabolites only in male rats. 1. Introduction Cisplatin (CP) is the most common antitumor drug in clinic. The most common side effect of CP is nephrotoxicity. However, hepatotoxicity and testicular toxicity are also frequently observed. CP is a platinum compound, which is accompanied by decrease in glomerular filtration rate (GFR), increase in blood urea nitrogen (BUN) and serum levels of creatinine, and tubular injury [1–3]. CP may disturb endothelium and endothelial function [4–7]. Nitric oxide (NO) is a marker of endothelial function. However, some studies documented that administration of CP increases the serum level of NO [8, 9], and on the other hand, increase of NO level may promote CP-induced nephrotoxicity [8]. NO is synthesized from the amino acid L-arginine by the endothelial NO synthase (eNOS) in endothelium. It is documented that L-arginine as precursor of NO has protective role against CP-induced nephrotoxicity [1, 3]. Some paradoxes could be seen here; CP may increase NO [1, 2], NO may promote CP-induced nephrotoxicity [8], and NO donates agents attenuating CP-induced nephrotoxicity [10]. NO is not a stable molecule, and its half life in circulation is considerably short, but it is rapidly oxidized to nitrite and nitrate that are considered as NO metabolites. The sum of NO metabolites called , and all
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