Altered modulation of soluble guanylate cyclase by nitric oxide in patients with liver disease.
The glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic moderate hyperammonemia either with or without liver failure. The impairment occurs at the level of activation of soluble guanylate cyclase by nitric oxide (NO). It has been suggested that the impairment of this pathway may be responsible for some of the neurological alterations found in hyperammonemia and hepatic encephalopathy. Soluble guanylate cyclase is also present in lymphocytes. Activation of guanylate cyclase by NO is also altered in lymphocytes from hyperammonemic rats or from rats with portacaval anastomosis. We assessed whether soluble guanylate cyclase activation was also altered in human patients with liver disease. We studied activation of soluble guanylate cyclase in lymphocytes from 77 patients with liver disease and 17 controls. The basal content of cGMP in lymphocytes was decreased both in patients with liver cirrhosis and in patients with chronic hepatitis. In contrast, cGMP concentration was increased in plasma from patients with liver disease. Activation of guanylate cyclase by NO was also altered in liver disease and was higher in lymphocytes from patients with cirrhosis or hepatitis than that in lymphocytes from controls. Successful treatment with interferon of patients with hepatitis C reversed all the above alterations. Altered modulation of soluble guanylate cyclase by NO in liver disease may play a role in the neurological and hemodynamic alterations in these patients.
Corbalán
R
R
Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, FVIB, Valencia, Spain.
Montoliu
C
C
Miñana
M D
MD
Del Olmo
J A
JA
Serra
M A
MA
Aparisi
L
L
Rodrigo
J M
JM
Felipo
V
V
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000201:enzymology; D008107:Liver Diseases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D012995:Solubility
D009569:Nitric Oxide; D018698:Glutamic Acid; D006162:Guanylate Cyclase; D006152:Cyclic GMP