Discrepant effects of inducible nitric oxide synthase modulation on systemic and splanchnic endothelial nitric oxide synthase activity and expression in cirrhotic rats.
BACKGROUND
Arterial vasodilatation, which is a major factor in the pathogenesis of the hyperkinetic circulatory state and portal hypertension in cirrhosis, is due to arterial nitric oxide (NO) overproduction secondary to endothelial NO synthase (eNOS) and inducible NOS (iNOS) upregulation. However, in cirrhosis, the respective roles of eNOS and iNOS isoforms in NO overproduction are still unknown and the effect of iNOS modulation on eNOS activity and expression has not been evaluated in the systemic or splanchnic vessels. The aim of this study was to evaluate the effects of modulating aortic and superior mesenteric arteries (SMA) iNOS on arterial eNOS activity and expression in rats with cirrhosis.


METHODS
eNOS and iNOS protein expression and eNOS activity (assessed by its phosphorylation at serine 1177) were measured in the aortas and SMA in untreated and treated cirrhotic rats with lipopolysaccharide (LPS), N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, and LPS plus L-NIL.


RESULTS
LPS administration significantly increased eNOS and iNOS protein expression and eNOS activity in the aortas of both sham-operated and cirrhotic rats. However, in SMA, LPS administration induced a decrease in eNOS protein expression and activity and an increase in iNOS protein expression.


CONCLUSIONS
The results of this study may explain the worsening of the hyperdynamic state in cirrhosis during septic shock by direct LPS-induced eNOS activation in large systemic vessels, and its inhibition in concomitant small splanchnic vasculature by iNOS synthesized NO.
Malyshev
Eugene
E
INSERM U773, Research Center Bichat Beaujon CRB3, Beaujon Hospital, Clichy, France.
Tazi
Khalid A
KA
Moreau
Richard
R
Lebrec
Didier
D
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000201:enzymology*; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D008239:Lysine