Interaction between flumazenil and the anesthetic effects of hexobarbital in the rat

Abstract

Interaction between flumazenil, a substance regarded mainly as a benzodiazepine antagonist, and an intravenous anesthetic barbiturate, hexobarbital, was investigated by using an electroencephalography threshold test in male rats. Flumazenil 10 mg/kg given as pretreatment reduced the threshold dose of hexobarbital approximately 20% indicating a synergistic interaction. Similar effects were obtained with the agonists, diazepam 20 mg/kg and lorazepam 2 mg/kg. Dose-response curve for flumazenil (2.5–10 mg/kg) was determined with the same technique and hexobarbital concentrations were analysed in serum and several brain regions at the threshold by high pressure liquid chromatography. Flumazenil 10 mg/kg pretreated group showed a different pattern of distribution of hexobarbital into the tested brain regions indicating a pharmacokinetic interaction. Low concentrations of hexobarbital in the brainstem which were negatively correlated with the dose of flumazenil indicate a pharmacodynamic interaction which could be due to a partial agonistic intrinsic activity of flumazenil, usually seen at much higher doses.