Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals.
BACKGROUND
The intravenous anesthetic etomidate is optically active and exists in two mirror-image enantiomeric forms. However, although the R(+) isomer is used as a clinical anesthetic, quantitative information on the relative potencies of the R(+) and S(-) isomers is lacking. These data could be used to test the relevance of putative molecular targets.


METHODS
The anesthetic concentrations for a half-maximal effect (EC50) needed to induce a loss of righting reflex in tadpoles (Rana temporaria) were determined for both etomidate enantiomers. The effects of the isomers on gamma-aminobutyric acid (GABA)-induced currents in stably transfected mouse fibroblast cells was also investigated using the patch-clamp technique. In addition, the effects of the isomers on a lipid chain-melting phase transition were determined.


RESULTS
The EC50 concentrations for general anesthesia for the R(+) and S(-) isomers were 3.4 +/- 0.1 microM and 57 +/- 1 microM, with slopes of n = 1.9 +/- 0.1 and n = 2.9 +/- 0.2, respectively. The R(+) isomer was also much more effective than the S(-) isomer at potentiating GABA-induced currents, although the degree of stereoselectivity varied with anesthetic concentration. R(+) etomidate potentiated the GABA-induced currents by increasing the apparent affinity of GABA for its receptor. Both isomers were equally effective at disrupting lipid bilayers.


CONCLUSIONS
These data are consistent with the idea that the GABA(A) receptor plays a central role in the actions of etomidate. Etomidate exerts its effects on the receptor by binding directly to a specific site or sites on the protein and allosterically enhancing the apparent affinity of GABA for its receptor.
Tomlin
S L
SL
Biophysics Section, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Jenkins
A
A
Lieb
W R
WR
Franks
N P
NP
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000737:chemistry* / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008051:Lipid Bilayers; D051379:Mice; D011896:Rana temporaria; D011963:Receptors, GABA-A / Q000187:drug effects*; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018686:Anesthetics, Intravenous; D008051:Lipid Bilayers; D011963:Receptors, GABA-A; D015060:1,2-Dipalmitoylphosphatidylcholine; D005680:gamma-Aminobutyric Acid; D005045:Etomidate