Hepatic encephalopathy in rats with thioacetamide-induced acute liver failure is not mediated by endogenous benzodiazepines.
BACKGROUND
To distinguish whether the improvement of hepatic encephalopathy by benzodiazepine receptor antagonists is mediated by their antagonistic or their inverse agonistic properties, the neurobehavioral effects of a variety of benzodiazepine receptor ligands in rats with thioacetamide-induced acute liver failure were tested.


METHODS
The neural inhibitory effect of the benzodiazepine agonist flunitrazepam and its reversibility by the "pure" antagonist Ro 14-7437 were examined in thioacetamide-treated rats and controls. The effects of Ro 14-7437, of the partial inverse agonist Ro 15-4513, and the inverse agonist DMCM in rats with hepatic encephalopathy grade II/III were tested. Encephalopathic rats were pretreated with Ro 14-7437 or vehicle and then injected with Ro 15-4513.


RESULTS
Thioacetamide-treated rats were more sensitive to flunitrazepam than controls. In both groups, its effect was completely antagonized with Ro 14-7437. Encephalopathy was significantly improved by Ro 15-4513, although Ro 14-7437 and vehicle had no effect. DMCM worsened the condition of encephalopathic rats but had no effect in controls. Pretreatment with Ro 14-7437 abolished the beneficial effects of Ro 15-4513.


CONCLUSIONS
In rats with thioacetamide-induced liver failure, endogenous benzodiazepines do not precipitate hepatic encephalopathy. The amelioration of hepatic encephalopathy is mediated by benzodiazepine receptor ligands with both antagonistic and inverse agonistic properties.
Püspök
A
A
Department of Gastroenterology and Hepatology, University of Vienna, Austria.
Herneth
A
A
Steindl
P
P
Ferenci
P
P
D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000209:etiology* / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000009:adverse effects*
D001386:Azides; D002243:Carbolines; D003292:Convulsants; D013853:Thioacetamide; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005445:Flunitrazepam; C038674:Ro 14-7437; C042957:Ro 15-4513