Inhibition by volatile anesthetics of endogenous glutamate release from synaptosomes by a presynaptic mechanism.
BACKGROUND
Synaptic transmission is more sensitive than axonal conduction to the effects of general anesthetics. Previous studies of the synaptic effects of general anesthetics have focused on postsynaptic sites of action. We now provide direct biochemical evidence for a presynaptic effect of volatile anesthetics on neurotransmitter release.


METHODS
Rat cerebrocortical synaptosomes (isolated presynaptic nerve terminals) were used to determine the effects of general anesthetics on the release of endogenous L-glutamate, the major fast excitatory neurotransmitter. Basal and evoked (by 4-aminopyridine, veratridine, increased KCl, or ionomycin) glutamate release were measured by continuous enzyme-coupled fluorometry.


RESULTS
Clinical concentrations of volatile halogenated anesthetics, but not of pentobarbital, inhibited 4-aminopyridine-evoked Ca(2+)-dependent glutamate release. Halothane also inhibited veratridine-evoked glutamate release but not basal, KCl-evoked, or ionomycin-evoked glutamate release. Halothane inhibited both the 4-aminopyridine-evoked and the KCl-evoked increase in free intrasynaptosomal [Ca2+].


CONCLUSIONS
Inhibition of glutamate release from presynaptic nerve terminals is a potential mechanism of volatile anesthetic action. Comparison of the sensitivity of glutamate release evoked by secretogogues that act at various steps in the neurotransmitter release process suggests that halothane does not affect Ca(2+)-secretion coupling or vesicle exocytosis but inhibits glutamate release at a step proximal to Ca2+ influx, perhaps by blocking presynaptic Na+ channels. Synaptosomal glutamate release evoked by 4-aminopyridine should provide a useful system for further characterization of the presynaptic effects of anesthetics.
Schlame
M
M
Department of Anesthesiology, Cornell University Medical College, New York, New York 10021, USA.
Hemmings
H C
HC
D015761:4-Aminopyridine / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects; D013574:Synaptosomes / Q000378:metabolism*; D014701:Veratridine / Q000494:pharmacology
D000777:Anesthetics; D015222:Sodium Channels; D018698:Glutamic Acid; D015759:Ionomycin; D011189:Potassium Chloride; D014701:Veratridine; D015761:4-Aminopyridine; D011493:Protein Kinase C; D002118:Calcium; D006221:Halothane