Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: Role of nitric oxide synthase isoforms
ABSTRACT 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.
- SourceAvailable from: Hui-Chun Huang
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ABSTRACT: Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.World Journal of Gastroenterology 08/2009; 15(25):3086-98. · 2.43 Impact Factor
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ABSTRACT: Hepatic encephalopathy is a common metabolic condition in children, having a significantly different aetiopathogenesis from that in adults. The present paper reviews the medical interventions of proven efficacy and also discusses recent advances from various fields as applicable to management of children with this disorder, focusing on measures other than liver transplant. The most important component of managing a child with hepatic encephalopathy is basic intensive care with regulation of fluid status, glucose and electrolyte homeostasis. Specific management includes measures to reduce serum ammonia concentrations, and the prevention and prompt treatment of complications. Methods to reduce ammonia target various steps in its metabolism. This includes reducing its production in and absorption from the intestine and promoting its metabolism in the liver. Significant secondary complications occurring in fulminant hepatic failure which require urgent recognition and management include coagulopathy, cerebral oedema and renal dysfunction. Children with hepatic encephalopathy also have several other paediatric care issues such as fever, requirement for sedation, etc, where the choice of drug is not straightforward and is often different from other settings. This is reviewed here along with an attempt to provide rational choices based on available evidence. Certain controversial and experimental approaches to treatment of fulminant hepatic failure are also discussed, but clearly delineated from the established management protocol. Finally, the role of artificial liver support devices is discussed, with the realisation that they can provide an effective bridge during the time when a patient is waiting for a suitable donor for liver transplant.Postgraduate medical journal 01/2010; 86(1011):34-41; quiz 40. DOI:10.1136/pgmj.2009.079467 · 1.55 Impact Factor