Effects of isoflurane and propofol on glutamate and GABA transporters in isolated cortical nerve terminals.
BACKGROUND
Depression of glutamate-mediated excitatory transmission and potentiation of gamma-aminobutyric acid (GABA)-mediated inhibitory transmission appear to be primary mechanisms by which general anesthetics produce anesthesia. Since effects on transmitter transport have been implicated in anesthetic actions, the authors examined the sensitivity of presynaptic glutamate and GABA transporters to the effects of a representative volatile (isoflurane) and a representative intravenous (propofol) anesthetic.


METHODS
A dual-isotope (l-[3H]glutamate and [14C]GABA) approach allowed simultaneous comparisons of anesthetic effects on three independent assays of glutamate and GABA transporters in adult rat cerebral cortex: transmitter uptake into isolated nerve terminals (synaptosomes), transmitter binding to lysed and washed synaptosomes (synaptic membranes), and carrier-mediated release (reverse transport) of transmitter from preloaded synaptosomes using a modified superfusion system.


RESULTS
Isoflurane produced small but statistically significant inhibition of l-[3H]glutamate and [14C]GABA uptake, while propofol had no effect. Inhibition of uptake by isoflurane was noncompetitive, an outcome that was mimicked by indirectly affecting transporter function through synaptosomal depolarization. Neither isoflurane nor propofol affected l-[3H]glutamate or [14C]GABA binding to synaptic membranes or Ca(2+)-independent carrier-mediated l-[3H]glutamate or [14C]GABA release (reverse transport).


CONCLUSIONS
These findings suggest that isoflurane and propofol at clinical concentrations do not affect excitatory glutamatergic transmission or inhibitory GABAergic transmission directly effects on their presynaptic neuronal transporters.
Westphalen
Robert I
RI
Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Hemmings
Hugh C
HC
D000465:Algorithms; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D027361:Organic Anion Transporters; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D007530:Isoflurane; D015742:Propofol