Abstract
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-evokedl-[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-evokedl-[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.
Footnotes
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This work was supported by a grant from the National Institutes of Health (GM 58055) and by the Department of Anesthesiology.
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DOI: 10.1124/jpet.102.044685
- Abbreviations:
- 4AP
- 4-aminopyridine
- FR
- fractional release
- Received September 27, 2002.
- Accepted December 4, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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