Background: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether β-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis. Methods: Nipradilol, a β-blocker with an ONO<sub>2</sub> group (5, 10 or 15 mg/kg/day) and propranolol, a β-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro- L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U<sub>NOx</sub>) and cyclic GMP (U<sub>cGMP</sub>). Results: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U<sub>NOx</sub> in comparison with the sham-operated rats. Nipradilol increased U<sub>NOx</sub> and U<sub>cGMP</sub> significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U<sub>NOx</sub>. The addition of nipradilol increased U<sub>NOx</sub> and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect. Conclusion: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The β-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.