The role of nitric oxide (NO) and oxygen free radicals in cyclosporine
(CsA) nephrotoxicity was investigated using L-arginine, an NO substra
te, and allopurinol, a xanthine oxidase inhibitor (involved in the for
mation of oxygen radicals) in an experimental model with Wistar rats.
CsA, administered at 15 mg/kg/body weight (BW) subcutaneously for 10 d
ays, caused a decrease in glomerular filtration rate, with inulin clea
rance of 0.33+/-0.04 vs. 1.11+/-0.06 ml/min/100 g BW (P<0.01 vs. contr
ol). L-Arginine, 1.5% in drinking water 5 days before and during CsA a
dministration partially protected the animals against this fall in glo
merular filtration rate, with inulin clearance of 0.68+/-0.03 ml/min/1
00 g BW (P<0.01 vs. CsA). Allopurinol, at 10 mg/kg/BW by gavage, also
had a protective action, with inulin clearance of 0.54+/-0.04 ml/min/1
00 g (P<0.01 vs. CsA). CsA caused an elevation in NO production, as as
sessed by urinary excretion of its metabolites, nitrite and nitrate (N
O2 and NO3; 0.836+/-0.358 vs. 0.107+/-0.019 nmol/mu g creatinine). NO
production was as much as threefold higher in the L-arginine group (1.
853+/-0.206 nmol/g creatinine). This CsA effect is probably related to
its vasoconstrictive stimulus. Supplementation with L-arginine, which
provides more substrate for NO formation, may enhance vasodilatation
and consequently reduce the impairment of renal function. The protecti
on provided by allopurinol may be related to the reduced formation of
oxygen radicals, preventing the deleterious effects of lipid peroxidat
ion.