Effect of molsidomine and l-arginine in cyclosporine nephrotoxicity: role of nitric oxide

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. To determine if the renal alterations are mediated directly by cyclosporine or by secondary homodynamic alterations induced by cyclosporine, we evaluated if l-arginine and a nitric oxide donor, molsidomine could prevent 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/kg, s.c. for 21 days), group 3 received CsA along with l-arginine (125 mg/kg in drinking water concurrently with CsA), groups 4 and 5 received CsA along with molsidomine (5 and 10 mg/kg, p.o. 24 h before and 21 days concurrently with CsA), group 6 received CsA along with l-arginine (125 mg/l in drinking water concurrently with CsA) and l-NAME (10 mg/kg), groups 7 and 8 received l-NAME (10 mg/kg) along with CsA and molsidomine (5 and 10 mg/kg), respectively. 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 by 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, significantly deranged the renal functions as well as renal morphology. Treatment with l-arginine as well as with molsidomine significantly improved the renal dysfunction; tissue and urine total nitric oxide levels, renal oxidative stress and prevented the alterations in renal morphology. This protection against CsA nephrotoxicity was attenuated by treatment with l-NAME, clearly indicating that NO plays a pivotal role in renoprotective effect of l-arginine and molsidomine against cyclosporine nephrotoxicity.