Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide‐induced fulminant hepatic failure

Abstract

Hepatic encephalopathy is a complex neuropsychiatric syndrome seen secondary to acute liver failure, chronic parenchymal liver disease, or portal-systemic anastomosis. Vasodilatation induced by nitric oxide (NO) may be involved in the development of hepatic coma. However, there are no comprehensive data concerning the effects of NO inhibition on the severity of hepatic encephalopathy. Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of thioacetamide (TAA, 350 mg kg-1 day-1) for 3 days. Rats were divided into two groups to receive either NG-nitro-L-arginine methyl ester (L-NAME, 20 mg kg-1 day-1 via intragastric gavage) or normal saline (N/S) from 2 days prior to TAA administration for 5 days. Severity of encephalopathy was assessed by counts of motor activity and neurobehaviour test scores. Plasma levels of endotoxin, tumour necrosis factor-alpha and nitrate/nitrite were determined by the chromogenic Limulus assay, enzyme-linked immunosorbent assay and colorimetric assay, respectively. Compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving L-NAME (59% vs. 18%, P < 0.01). Inhibition of NO had detrimental effects on the counts of motor activities (P < 0.05) and neurobehaviour score (P < 0.01). Rats treated with L-NAME had significantly higher plasma levels of endotoxin (26.7 +/- 3.8 pg mL-1) and tumour necrosis factor-alpha (29.4 +/- 6.5 pg mL-1) compared with rats treated with N/S (13.2 +/- 2.7 pg mL-1 and 11.2 +/- 2.6 pg mL-1, respectively, P < 0.01). Plasma levels of endotoxin and tumour necrosis factor-alpha, but not of nitrate/nitrite, were significantly correlated with the severity of hepatic encephalopathy (P < 0.05). Chronic L-NAME administration had detrimental effects on the severity of encephalopathy in TAA-treated rats, suggesting a protective role of NO in the development of fulminant hepatic failure.

Lack of detrimental effects of nitric oxide inhibition in bile duct‐ligated rats with hepatic encephalopathy

“…We recently reported that chronic administration of N ω -nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, in rats with FHF had deleterious effects on HE as measured by the mortality rate and motor activity counts [20]. We recently reported that chronic administration of N ω -nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, in rats with FHF had deleterious effects on HE as measured by the mortality rate and motor activity counts [20].…”

Thioacetamide-induced liver regeneration involves the expression of cyclooxygenase 2 and nitric oxide synthase 2 in hepatocytes

“…Inhibition of NOS-2 with aminoguanidine decreased the serum levels of AST after TAM treatment and this compound did not change parameters concerning hepatocellular regeneration [40]. However, different reports demonstrated that liver regeneration is impaired in NOS-2 KO mice [14,41] and that NOS-2 inhibition causes detrimental effects on hepatic encephalopathy induced by TAM [42]. Therefore, it appears that NO plays an important role in liver regeneration after acute hepatotoxic treatment, probably because NO protects surviving cells from cytokinemediated cell death, favors hepatic circulation and contributes to the angiogenic activity in the remnant tissue.…”

Portosystemic collaterals are not prerequisites for the development of hepatic encephalopathy in cirrhotic rats

“…21,22 However, insufficient liver functions and the presence of portosystemic collaterals, which result in the failure to metabolize toxic substances derived from the gastrointestinal tract, are considered fundamental to HE. Common animal models used to study HE include models of fulminant hepatic failure 23,24 and portacaval shunts. 25,26 To investigate the pathogenesis of HE, the early detection of neurological and behavioral disturbances in these animals is crucial.…”