Etomidate reduces glutamate uptake in rat cultured glial cells: involvement of PKA.
OBJECTIVE
Glutamate is the main excitatory neurotransmitter in the vertebrate CNS. Removal of the transmitter from the synaptic cleft by glial and neuronal glutamate transporters (GLTs) has an important function in terminating glutamatergic neurotransmission and neurological disorders. Five distinct excitatory amino-acid transporters have been characterized, among which the glial transporters excitatory amino-acid transporter 1 (EAAT1) (glutamate aspartate transporter) and EAAT2 (GLT1) are most important for the removal of extracellular glutamate. The purpose of this study was to describe the effect of the commonly used anaesthetic etomidate on glutamate uptake in cultures of glial cells.


METHODS
The activity of the transporters was determined electrophysiologically using the whole cell configuration of the patch-clamp recording technique.


RESULTS
Glutamate uptake was suppressed by etomidate (3-100 microM) in a time- and concentration-dependent manner with a half-maximum effect occurring at 2.4+/-0.6 microM. Maximum inhibition was approximately 50% with respect to the control. Etomidate led to a significant decrease of V(max) whereas the K(m) of the transporter was unaffected. In all cases, suppression of glutamate uptake was reversible within a few minutes upon washout. Furthermore, both GF 109203X, a nonselective inhibitor of PKs, and H89, a selective blocker of PKA, completely abolished the inhibitory effect of etomidate.


CONCLUSIONS
Inhibition of glutamate uptake by etomidate at clinically relevant concentrations may affect glutamatergic neurotransmission by increasing the glutamate concentration in the synaptic cleft and may compromise patients suffering from acute or chronic neurological disorders such as CNS trauma or epilepsy.
Räth
M
M
University Clinic of Anesthesiology, Steinhoevelstrasse 9, Ulm, Germany.
Föhr
K J
KJ
Weigt
H U
HU
Gauss
A
A
Engele
J
J
Georgieff
M
M
Köster
S
S
Adolph
O
O
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018686:Anesthetics, Intravenous; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D005045:Etomidate