Nitric oxide (NO), an L-arginine derivative, is implicated in neuronal transmission, immune response and vasodilation, besides acting as a platelet function modulator. A number of recent studies in the experimental model of renal mass reduction (RMR) in rats have proposed the hypothesis that abnormalities of the NO synthetic pathway could have a key role in mediating the complex hemodynamic and hemostatic disorders associated with the progression of renal disease. Thus, renal NO generation is lower than normal in rats with RMR seven days after surgery, and progressively worsens with time in close correlation with signs of renal injury. This abnormality is due to a strong defect of inducible NO synthase (iNOS) content in the kidney. In the same model, administration of either the NO precursor, L-arginine, or a NO-releasing compound reduces proteinuria, slows renal disease progression and prolongs survival. On the other hand RMR is associated with a progressive increase of renal synthesis of the potent vasoconstrictor peptide, endothelin-1 (ET-1), whose mRNA is expressed in excessive amounts in cortical tubules early after surgical ablation. In this setting, a marked reduction of NO, in the face of continuous local generation of ET-1, may well contribute to intraglomerular capillary hypertension and cell proliferation. Actually, administration of a selective ETA receptor antagonist to RMR rats reduced abnormal permeability to proteins and prevented renal function deterioration. In the same model the ETA receptor antagonist also corrected the impaired renal NO synthesis, suggesting that excessive ET-1 bioactivity might also be responsible for the progressive reduction of renal NO. In keeping with this possibility are recent in vitro data that ET-1 inhibits iNOS transcription, a process mediated by interaction of the peptide with subtype A receptors. Nitric oxide and ET-1 have profound and opposite effects on glomerular and tubular function. Thus, abnormalities of renal NO and ET-1 synthetic pathways, as documented in the RMR model, likely have major and complementary roles in promoting alteration in renal hemodynamics and functions in progressive nephropathies.