Altered modulation of soluble guanylate cyclase in lymphocytes from patients with liver disease.

Studies of animal models suggest that the activation of soluble guanylate cyclase by nitric oxide is altered in liver disease. We studied 77 patients with liver disease and 17 controls, to investigate whether the activation of soluble guanylate cyclase is altered in lymphocytes from patients with liver disease. The basal content of guanosine 3',5'-cyclic monophosphate (cGMP) in lymphocytes was decreased both in patients with liver cirrhosis (by 52%) and in patients with chronic hepatitis (by 62%). Activation of soluble guanylate cyclase by nitric oxide was higher in lymphocytes from patients with cirrhosis (3100+/-1000% of basal) or with hepatitis (5200+/-2500% of basal) than in lymphocytes from controls (1200+/-500% of basal). cGMP in plasma was increased in patients with liver disease. Successful (but not unsuccessful) treatment with interferon of patients with hepatitis due to virus C reversed all the above alterations. Altered modulation of soluble guanylate cyclase by nitric oxide in liver disease may play a role in the hemodynamic alterations found in these patients.

Chronic hyperammonemia alters protein phosphorylation and glutamate receptor-associated signal transduction in brain.

There is substantial evidence that hyperammonemia is one of the main factors contributing to the neurological alterations found in hepatic encephalopathy. The mechanisms by which chronic moderate hyperammonemia affects brain function involves alterations in neurotransmission at different steps. This article reviews the effects of hyperammonemia on phosphorylation of key brain proteins involved in neurotransmission (the microtubule-associated protein (MAP-2), Na+/K+-ATPase and NMDA receptors). The physiological function of these proteins is modulated by phosphorylation and its altered phosphorylation in hyperammonemia may contribute to impairment of neurotransmission. The effects of chronic hyperammonemia on signal transduction pathways associated to glutamate receptors, such as the glutamate-nitric oxide (NO)-cGMP pathway, are also reviewed. The possible contribution of the impairment of this pathway in brain in vivo to the neurological alterations present in patients with hepatic encephalopathy is discussed.

Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients.

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from experimental animals with hyperammonemia with or without liver failure. The aim of this work was to assess the content and modulation of sGC in brain in chronic liver failure in humans. Expression of the alpha-1, alpha-2, and beta-1 subunits of sGC was measured by immunoblotting in autopsied frontal cortex and cerebellum from cirrhotic patients and controls. The contents of alpha-1 and alpha-2 subunits of guanylate cyclase was increased both in cortex and cerebellum, whereas the beta-1 subunit was not affected. Addition of the NO-generating agent S-nitroso-N-acetyl-penicillamine (SNAP) to homogenates of frontal cortex from controls increased the activity of sGC 87-fold, whereas, in homogenates from cirrhotic patients, the increase was significantly higher (183-fold). In contrast, in cerebellum, activation of guanylate cyclase by NO was significantly lower in patients (156-fold) than in controls (248-fold). A similar regional difference was found in rats with portacaval anastomosis. In conclusion, these findings show that the NO-guanylate cyclase signal transduction pathway is strongly altered in brain in patients with chronic liver failure and that the effects are different in different brain areas. Given that activation of sGC by NO in brain is involved in the modulation of important cerebral processes such as intercellular communication, learning and memory, and the sleep-wake cycle, these changes could be implicated in the pathogenesis of hepatic encephalopathy in these patients.