ROLE OF NO IN CYCLOSPORINE NEPHROTOXICITY - EFFECTS OF CHRONIC NO INHIBITION AND NO SYNTHESES GENE-EXPRESSION

The role of nitric oxide (NO) during cyclosporin renal vasoconstrictio n was evaluated by glomerular hemodynamic and histological changes pro duced by chronic NO synthesis inhibition and neuronal (nNOS), inducibl e (iNOS), and endothelial (eNOS) NO synthases mRNA expression in renal cortex and medulla. Uninephrectomized rats treated during 7 days with vehicle (Veh), cyclosporin A (CsA) 30 mg/kg, CsA + nitro-L-arginine m ethyl ester (L-NAME), and Veh + L-NAME (10 mg/dl) in the drinking wate r were studied. Increase in arterial pressure and afferent and efferen t resistances, as well as decrease in glomerular plasma flow, ultrafil tration coefficient, and single-nephron glomerular filtration rate wer e significantly greater with CsA + L-NAME than with CsA alone. The inc rease in afferent resistance was higher with CsA + L-NAME than with Ve h + L-NAME. In addition, glomerular thrombosis, proximal tubular vacuo lization, and arteriolar thickening were more prominent. In renal cort ex, eNOS mRNA expression exhibited a 2.7-fold increase in CsA, whereas , in medulla, nNOS and iNOS expression were lower in CsA than in Veh, while eNOS tended to increase. Our results support the hypothesis that NO synthesis is enhanced at cortical level during CsA nephrotoxicity, counterbalancing predominantly preglomerular vasoconstriction. Higher NO production could be the result of increased eNOS mRNA expression.