Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: Role of nitric oxide synthase isoforms
Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats.
Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay.
Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01).
Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.
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ABSTRACT: Fulminant hepatic failure (FHF) is a very serious clinical síndrome that, in spite of the important therapeutical advances that have taken place in the last years by means of bioartifical hepatic support devices and hepatic transplantation, is still associated to a high mortality. Knowledge and treatment of the FHF have been limited by the lack of satisfactory animal models. Among the attempts to develop a suitable model are surgical models, such as hepatectomy and total and/or partial devascularization, or the use of chemical substances with hepatic toxicity, such as acetaminophen, azoximethane, galactosamine or thioacetamide, among others. However, most of these models do not adequatly reflect the pattern of the human disease and all of them present important limitations. Although viral hepatitis is one of the most frequent causes of FHF, the use of viral agents to develop animal models has been little and unfortunate. Our group has recently developed a viral animal model of FHF by means of the inoculation of rabbits with the virus of the rabbit hemorrhagic disease. This model displays biochemical, and histological characteristics, and clinical signs that ressemble those in human FHF. In the present article, the most widely used animal models of FHF, together with their main advantages and disadvantages, are presented.
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