Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats.
The present study investigated sodium balance and renal tubular function in cirrhotic rats with chronic blockade of the nitric oxide (NO) system. Rats were treated with the nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) starting on the day of common bile duct ligation (CBL). Three weeks of daily sodium balance studies showed that CBL rats developed sodium retention compared with sham-operated rats and that l-NAME treatment dose dependently deteriorated cumulative sodium balance by reducing urinary sodium excretion. Five weeks after CBL, renal clearance studies were performed, followed by Western blotting of the electroneutral type 3 sodium/proton exchanger (NHE3) and the Na-K-ATPase present in proximal tubules. Untreated CBL rats showed a decreased proximal reabsorption with a concomitant reduction of NHE3 and Na-K-ATPase levels, indicating that tubular segments distal to the proximal tubules were responsible for the increased sodium reabsorption. l-NAME-treated CBL rats showed an increased proximal reabsorption measured by the lithium clearance method and showed a marked increase in NHE3 and Na-K-ATPase protein levels. Our results show that chronic l-NAME treatment exacerbates the sodium retention found in CBL rats by a significant increase in proximal tubular reabsorption.
Graebe
Martin
M
Department of Pharmacology, University of Copenhagen, DK-2200 Copenhagen N, Denmark. fimg@farmakol.ku.dk
Brond
Lone
L
Christensen
Sten
S
Nielsen
Soren
S
Olsen
Niels V
NV
Jonassen
Thomas E N
TE
D000450:Aldosterone / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D003135:Common Bile Duct; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000503:physiopathology; D008026:Ligation; D008094:Lithium / Q000493:pharmacokinetics; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
D004791:Enzyme Inhibitors; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000450:Aldosterone; D008094:Lithium; D012964:Sodium; D019001:Nitric Oxide Synthase; D000254:Sodium-Potassium-Exchanging ATPase; D019331:NG-Nitroarginine Methyl Ester