Nifedipine attenuates changes in nitric oxide levels, renal oxidative stress, and nephrotoxicity induced by cyclosporine.

ABSTRACT

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. The causes for the nephrotoxicity of CsA have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. To determine if the renal alterations are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if nifedipine prevents these alterations. Eight groups of rats were employed in this study, group 1 served as control, group 2 rats were treated with CsA (20 mg/mL, s.c. for 21 days), groups 3, 4, and 5 received CsA along with various doses of nifedipine (5, 10, and 20 mg/kg, p.o.) 24 h before and 21 days concurrently, groups 6, 7, and 8 received L-NAME (10 mg/kg i.p.), propranolol (10 mg/kg i.p.), and aminoguanidine (100 mg/kg p.o.), respectively, along with CsA. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, and urea clearance. Tissue and urine nitrite and nitrate levels were measured to estimate the total nitric oxide levels. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and enzymatic activity of catalase and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress, and significantly deranged the renal functions as well as renal morphology. Treatment with nifedipine (10, 20 mg/kg) significantly improved the renal dysfunction, tissue and urine total nitric oxide levels, and renal oxidative stress and prevented the alterations in renal morphology. These results clearly demonstrate that nifedipine is beneficial as a protective agent against nephrotoxicity induced by CsA, and the protection afforded by nifedipine appears to be mediated by an increase in endothelial nitric oxide release.