Chronic blockade of nitric oxide synthesis increases urinary endothelin-1 excretion.
OBJECTIVE
Our objective was to determine the effect of nitric oxide (NO) inhibition on renal synthesis of endothelin-1 (ET-1) in vivo.


METHODS
Rats were administered 500 mg/l 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.


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-1 is secondary to L-NAME-induced renal hyperfiltration injury.
Nakamura
T
T
Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Ohyama
Y
Y
Masuda
H
H
Kurashina
T
T
Saito
Y
Y
Kato
T
T
Sumino
H
H
Sato
K
K
Sakamaki
T
T
Sasaki
A
A
Nagai
R
R
D000419:Albuminuria / Q000139:chemically induced; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000652:urine*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester