Chronic blockade of nitric oxide synthesis increases urinary endothelin-1 excretion.

Objectives Our objective was to determine the effect of nitric oxide (NO) inhibition on renal synthesis of endothelin-l (ET-1) in vivo. Design and methods Rats were administered 500 mg/l N-G-nitro-L-arginine methyl ester (L-NAME) in their drinking water or its vehicle for 2 weeks (PW-L-NAME, n=10; SW-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, Results 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. Conclusions 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-l is secondary to L-NAME-induced renal hyperfiltration injury.