Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil.

Therapeutic modulation of the increased GABAergic tone in chronic hepatic encephalopathy (HE) by the benzodiazepine receptor (BR) antagonist flumazenil (F) has led to conflicting results in humans and animal models for HE. The BR inverse agonist sarmazenil (S) has only been used in animal models of acute HE. Therefore we investigated the effects of intravenous injection of F and S in dogs with chronic HE 8 to 12 weeks after placement of a portocaval shunt and 40% hepatectomy (n=7), compared to sham-operated pair-fed controls (n=7). The HE dogs had hyperammonemia (298 +/- 48 microM v 33 +/- 3 before surgery (mean +/- SEM)) and signs of HE at the start of the experiments (0.9 +/- 0.1 (scale 0-4)). Three (S3) and 8 (S8) mg/kg of S resulted in a significant improvement of encephalopathy (grade 0.9 +/- 0.2 immediately before v 0.5 +/- 0.1 after injection (S3) and 0.7 +/- 0.1 v 0.3 +/- 0.1 (S8)) and increase in mean dominant frequency of the EEG (MDF; 9.1 +/- 0.7 Hz v 11.1 +/- 0.3 (S3) and 8.9 +/- 0.5 v 11.0 +/- 0.3 (S8)) in HE dogs, whereas 15 mg/kg of S, 3 and 8 mg/kg of F, and the vehicle had no significant effects. The efficacy of S in these dogs is consistent with an increased GABAergic tone in the pathogenesis of chronic HE. The lack of effects of F makes a role for endogenous benzodiazepines herein unlikely.