Possible Interaction: Etomidate and Gamma-Aminobutyric Acid

“Background:Most anesthetics, particularly intravenous agents such as propofol and etomidate , enhance the actions of the neurotransmitter & ggr;-aminobutyric acid (GABA) at the GABA type A receptor.”

“Neurosteroids, barbiturates, and etomidate both potentiate responses to GABA and allosterically activate the receptor.”

“ Etomidate (3.2 μM) reduced GABA EC50 much less in α1M236Wβ2γ2L receptors (2-fold) than in wild type (23-fold).”

“The actions of etomidate at RdlM314N receptors exhibited an enantioselectivity common to that found for mammalian receptors, with 100 μMR‐(+)‐etomidate and S‐(−)‐etomidate enhancing the current induced by GABA (EC10) to 52±6% and 12±1% of the GABA maximum respectively.”

“Thus, depressant barbiturates, nonbarbiturate hypnotics (like etomidate ) and pyrazolopyridines (like etazolate), while inhibiting the binding of alpha-dihydropicrotoxinin (DHP), enhance the binding of GABA and benzodiazepines.”

“Although etomidate increases the desensitization of α4β3δ receptors, the pseudo steady-state current amplitude at 1 μM GABA is augmented by etomidate.”

“ Etomidate also increases the extent of desensitization and prolongs the deactivation of α4β3δ receptors in the presence of maximally activating concentrations of GABA (1 mM).”

“Our data demonstrate that etomidate enhances the pseudo steady-state current of α4β3δ receptors evoked by a GABA concentration comparable to an ambient GABA level, suggesting that α4β3δ receptors may mediate etomidate’s anesthetic effect in the brain.”

“During prolonged GABA applications, etomidate enhanced steady-state currents more than peak currents.”

“In αβγ receptors, etomidate enhances apparent GABA sensitivity (reduces GABA EC50), modestly increases maximal GABA efficacy, and slows current deactivation without affecting desensitization (Zhong et al., 2008).”

“In αβδ receptors characterized by low GABA efficacy, etomidate dramatically increases responses to both low and maximal GABA.”

“Increasing GABA efficacy on alpha4/6beta3delta and alpha4beta3 receptors is likely to make an important contribution to the anesthetic effects of etomidate , propofol and the neurosteroid THDOC.”

“Results:IL-1&bgr; increased the amplitude of current evoked by GABA in combination with clinically relevant concentrations of either etomidate (3 &mgr;M) or isoflurane (250 &mgr;M) (n = 5 to 17, P < 0.05).”

“At the GABA(A) receptor, low concentrations of etomidate potentiate the inhibitory effect of GABA on specific binding of the closed channel ligand [(3)H]ethynylpropylbicycloorthobenzoate ([(3)H]EBOB).”