Submitted on February 27, 2003
Accepted on October 17, 2003
Chronic Nitric Oxide Synthase Inhibition Exacerbates Renal Dysfunction in Cirrhotic Rats
Martin Graebe1*, Lone Brond1, Sten Christensen1, Soren Nielsen2, Niels V. Olsen3, and Thomas E.N. Jonassen1
1 Department of Pharmacology, University of Copenhagen, Copenhagen, DK-2200, Denmark
2 Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, DK-8000, Denmark
3 Department of Pharmacology, University of Copenhagen, Copenhagen, DK-2200, Denmark; Department of Neuroanesthesia, The Neuroscience Center, University of Copenhagen, Copenhagen, DK-2200, Denmark
* To whom correspondence should be addressed. E-mail: fimg{at}farmakol.ku.dk.
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 non-selective NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) starting on the day of common bile duct ligation (CBL). Three weeks daily sodium balance studies showed that CBL rats developed sodium retention compared to 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 electro-neutral 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. LNAME treated CBL rats showed an increased proximal reabsorption measured by the lithium clearance method and showed a marked increase of the 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.
