Midazolam and ketamine inhibit glutamate release via a cloned human brain glutamate transporter.
OBJECTIVE
In cerebral ischemia/anoxia, the glutamate transporter runs in reverse and releases glutamate into the extracellular space, causing irreversible neuronal damage. Intravenous anesthetics attenuate overall glutamate release and prevent neuronal injury during anoxia/ischemia, but their effect on the glutamate transporter is variable.


METHODS
A human glial glutamate transporter (hGLT-I) cDNA was isolated by screening a human cerebral cortical library. Cloned cDNA was transfected in Chinese hamster ovary cells. The effect of the intravenous anesthetics midazolam (0.3 to 30 microM), ketamine (10 to 100 microM), thiopental (30 to 300 microM), and propofol (3 to 30 microM) on reversed uptake of L-glutamate via hGLT-I was examined by whole-cell patch-clamp.


RESULTS
Midazolam at a concentration 3 microM reduced outward currents arising from reversed L-glutamate uptake via hGLT-I in a concentration-dependent manner. While, ketamine at 100 microM attenuated the same outward currents, to 53.3+/-11.4% of those seen in controls without anesthetics (P<0.05, n=5). In contrast, neither thiopental nor propofol showed effects on outward currents mediated by reversed operation of hGLT-I.


CONCLUSIONS
These results suggest that midazolam and ketamine, but not thiopental and propofol, have a capacity to inhibit glutamate release via GLT- I directly.
Sakai
F
F
Department of Anesthesiology and Critical Care Medicine, Tokyo Medical and Dental, University, Japan. sakai.mane@med.tmd.ac.jp
Amaha
K
K
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000502:physiology; D027322:Amino Acid Transport System X-AG; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008874:Midazolam / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000777:Anesthetics; D015221:Potassium Channels; D011994:Recombinant Proteins; D018698:Glutamic Acid; D007649:Ketamine; D008874:Midazolam