High-dose flumazenil potentiates the hypnotic activity of propofol, but not that of thiopental, in ddY mice.
BACKGROUND
Flumazenil is a specific benzodiazepine agonist, which is reported to have a partial benzodiazepine agonist-like effect at a high dose. This study investigated the effects of flumazenil and midazolam on the hypnotic dose of propofol and thiopental in ddY mice, using a behavioral model.


METHODS
Mice were given either propofol or thiopental intravenously to induce hypnosis, which was defined as a loss of the righting reflex. The mice were pre-treated with flumazenil (0.05, 0.1, or 0.2 mg kg(-1)) or midazolam (0.1 or 0.2 mg kg(-1)), and given propofol or thiopental after a 30-s delay.


RESULTS
Pre-treatment with flumazenil (0.1 or 0.2 mg kg(-1)) significantly decreased the hypnotic dose of propofol compared to the control group (9.3+/-0.39 [8.5-10.0] or 9.0+/-0.28 [8.5-9.6] vs. 10.8+/-0.42 [9.9-11.6] mg kg(-1) (ED50+/-SEM and [95% confidence interval]) P<0.05), but not that of thiopental (9.1+/-0.30 [8.5-9.7] with 0.2 mg kg(-1) flumazenil vs. 9.3+/-0.42 [8.4-10.1] mg kg(-1) with saline). Midazolam reduced the hypnotic dose of both propofol and thiopental. Flumazenil antagonized the potentiating effect of midazolam (0.2 mg kg(-1)) on the hypnotic activity of propofol.


CONCLUSIONS
These results suggest that the hypnotic activity of propofol is potentiated by the partial agonist activity of flumazenil in ddY mice.
Adachi
Y U
YU
Department of Anesthesiology, National Defense Medical College, Tokorozawa, Saitama, Japan. grd1117@gr.ndmc.ac.jp
Watanabe
K
K
Higuchi
H
H
Satoh
T
T
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D013874:Thiopental / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D005442:Flumazenil; D013874:Thiopental; D008874:Midazolam; D015742:Propofol