Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors.
The intravenous general anaesthetic propofol (2,6-di-isopropylphenol) is frequently combined with a benzodiazepine. There are clinical reports of synergism between these two agents for induction of general anaesthesia. To investigate a possible mechanism of this synergistic interaction between propofol and benzodiazepines, the effect of propofol and flurazepam on GABAA receptor function was examined in Xenopus oocytes expressing recombinant alpha 1 beta 2 gamma 2L and alpha 2 beta 2 gamma 2L receptor constructs. Potentiation of GABA receptor-activated current by low (1-10 microM) concentrations of propofol together with flurazepam (0.25-0.5 microM) was significantly greater than predicted by an additive response. Isobolographic analysis indicated a strong synergistic interaction between propofol and flurazepam at either of the receptor constructs examined. In contrast, the cyclopyrrolone derivative zopiclone, which produced a similar facilitation of GABA receptor-activated current compared to flurazepam, produced a less than additive potentiation when combined with propofol. Flurazepam significantly decreased the EC50 concentration of propofol for potentiation of GABA responses. Thus, flurazepam, in addition to facilitating GABA receptor activity on its own, also increases on its own, also increases the apparent affinity of the GABAA receptor complex to propofol, resulting in a greater than expected potentiation by the combination of propofol plus flurazepam.
Reynolds
J N
JN
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Maitra
R
R
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D053961:Azabicyclo Compounds; D004357:Drug Synergism; D004594:Electrophysiology; D005260:Female; D005479:Flurazepam / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology*; D018079:Receptors, GABA / Q000187:drug effects*; D014981:Xenopus
D018686:Anesthetics, Intravenous; D053961:Azabicyclo Compounds; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D010879:Piperazines; D018079:Receptors, GABA; C515050:zopiclone; D005479:Flurazepam; D015742:Propofol