Differential effects of selective and non-selective NOS inhibition on renal arginine and protein metabolism during endotoxemia in rats.
OBJECTIVE
The kidney is the main endogenous producer of circulating arginine. Renal arginine disposal is directed to protein synthesis, urea production and nitric oxide synthesis. The administration of nitric oxide synthase inhibitors during sepsis may be beneficial or detrimental depending on the specificity of the inhibitor. We aimed to measure the effects of two NOS inhibitors, with different specificity, on renal arginine and protein turnover in a rat model of sepsis.


METHODS
Rats were subject to double hit endotoxemia and either L-NAME (non-specific), SMT (iNOS specific) or saline. Under anesthesia, vessels supplying and draining the kidney were catheterized. Systemic and intra-renal arginine and protein metabolism were measured using a primed continuous infusion of L-[2,3-(3)H]arginine and L-[2,6-(3)H]phenylalanine.


RESULTS
Non-specific NOS reduced systemic protein and arginine turnover, whereas selective iNOS inhibition did not. In the kidney, blood flow was reduced by L-NAME, but not by SMT. In conjunction with this, non-selective NOS inhibition increased renal protein breakdown, whereas selective iNOS inhibition increased renal arginine production.


CONCLUSIONS
This study shows that non-selective NOS inhibition using L-NAME is detrimental for systemic and renal protein metabolism. Selective NOS inhibition stimulates renal arginine synthesis, without changing circulating arginine levels.
Hallemeesch
M M
MM
Department of Surgery, Maastricht University, Maastricht, The Netherlands.
Cobben
D C P
DC
Soeters
P B
PB
Deutz
N E P
NE
D000818:Animals; D001120:Arginine / Q000096:biosynthesis* / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
D004791:Enzyme Inhibitors; D011506:Proteins; D007550:Isothiuronium; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; D019331:NG-Nitroarginine Methyl Ester