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Vol. 304, Issue 3, 1188-1196, March 2003
Departments of Anesthesiology and Pharmacology, Weill Medical
College of Cornell University, New York, New York
The role of presynaptic mechanisms in general anesthetic depression of
excitatory glutamatergic neurotransmission and facilitation of
GABA-mediated inhibitory neurotransmission is unclear. A dual isotope
method allowed simultaneous comparisons of the effects of a
representative volatile (isoflurane) and intravenous (propofol) anesthetic on the release of glutamate and GABA from isolated rat
cerebrocortical nerve terminals (synaptosomes). Synaptosomes were
prelabeled with L-[3H]glutamate and
[14C]GABA, and release was determined by superfusion with
pulses of 30 mM K+ or 1 mM 4-aminopyridine (4AP) in the
absence or presence of 1.9 mM free Ca2+. Isoflurane
maximally inhibited Ca2+-dependent 4AP-evoked
L-[3H]glutamate release (99 ± 8%
inhibition) to a greater extent than [14C]GABA release
(74 ± 6% inhibition; P = 0.023). Greater
inhibition of L-[3H]glutamate versus
[14C]GABA release was also observed for the
Na+ channel antagonists tetrodotoxin (99 ± 4 versus
63 ± 5% inhibition; P < 0.001) and riluzole
(84 ± 5 versus 52 ± 12% inhibition; P = 0.041). Propofol did not differ in its maximum inhibition of Ca2+-dependent 4AP-evoked
L-[3H]glutamate release (76 ± 12%
inhibition) compared with [14C]GABA (84 ± 31%
inhibition; P = 0.99) release. Neither isoflurane (1 mM) nor propofol (15 µM) affected K+-evoked release,
consistent with a molecular target upstream of the synaptic vesicle
exocytotic machinery or voltage-gated Ca2+ channels coupled
to transmitter release. These findings support selective presynaptic
depression of excitatory versus inhibitory neurotransmission by
clinical concentrations of isoflurane, probably as a result of
Na+ channel blockade.
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