L-Arginine and allopurinol protect against cyclosporine nephrotoxicity.
The role of nitric oxide (NO) and oxygen free radicals in cyclosporine (CsA) nephrotoxicity was investigated using L-arginine, an NO substrate, and allopurinol, a xanthine oxidase inhibitor (involved in the formation of oxygen radicals) in an experimental model with Wistar rats. CsA, administered at 15 mg/kg/body weight (BW) subcutaneously for 10 days, caused a decrease in glomerular filtration rate, with inulin clearance of 0.33+/-0.04 vs. 1.11+/-0.06 ml/min/100 g BW (P<0.01 vs. control). L-Arginine, 1.5% in drinking water 5 days before and during CsA administration, partially protected the animals against this fall in glomerular filtration rate, with inulin clearance of 0.68+/-0.03 ml/min/100 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/100 g (P<0.01 vs. CsA). CsA caused an elevation in NO production, as assessed by urinary excretion of its metabolites, nitrite and nitrate (NO2 and NO3; 0.836+/-0.358 vs. 0.107+/-0.019 nmol/microg 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 protection provided by allopurinol may be related to the reduced formation of oxygen radicals, preventing the deleterious effects of lipid peroxidation.
Assis
S M
SM
Laboratorio de Investigação Medica, Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, Brazil.
Monteiro
J L
JL
Seguro
A C
AC
D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D016572:Cyclosporine / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007444:Inulin / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000502:physiology; D009573:Nitrites / Q000652:urine; D011188:Potassium / Q000652:urine; D051381:Rats; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D000493:Allopurinol; D016572:Cyclosporine; D007444:Inulin; D001120:Arginine; D014969:Xanthine Oxidase; D011188:Potassium