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Our objective was to determine the effect of nitric oxide (NO) inhibition on renal synthesis of endothelin-1 (ET-1) in vivo.Rats were administered 500 mg/1 NG-nitro-L-arginine methyl ester (L-NAME) in their drinking water or its vehicle for 2 weeks (2W-L-NAME, n = 10; 2W-CONT, n = 10) or for 6 weeks (6W-L-NAME, n = 13; 6W-CONT, n = 11). We measured the levels of albumin, NO metabolites and ET-1 both in their blood and in 24 h urine samples, and determined the expression of preproET-1 messenger RNA in the renal cortex and the inner medulla. We also examined renal histology.L-NAME administration for 6 weeks reduced NO metabolites both in serum (21.5 versus 3.66 nmol/ml in 6W-CONT) and in urine (5.72 versus 22.53 nmol/24 h in 6W-CONT), raised the systolic blood pressure (228 versus 162 mmHg in 6W-CONT), and the increased urinary excretion of albumin (24.29 ± 11.66 versus 0.60 ± 0.08 mg/day in 6W-CONT) and of ET-1 (112.0 ± 38.3 versus 35.8 ± 4.4 pg/day in 6W-CONT). There were no significant differences between the plasma levels of ET-1 in the control and L-NAME groups. Expression of preproET-1 messenger RNA increased in the renal cortex but not in the inner medulla in the 6W-L-NAME group. Bleeding and marked arteriolar narrowing were observed in the renal cortex of the 6W-L-NAME group.Prolonged inhibition of NO synthesis increases urinary excretion of ET-1 and albumin without having any effect on plasma ET-1 levels. These results do not support the hypothesis that NO plays an inhibitory role in the regulation of ET-1 in the systemic circulation, although it is possible that such a role could exist in renal tissue. However, in view of the albuminuria, a more likely explanation is that increased urinary ET-1 is secondary to L-NAME-induced renal hyperfiltration injury.