Journal
BRITISH JOURNAL OF ANAESTHESIA
Volume 110, Issue 4, Pages 592-599Publisher
ELSEVIER SCI LTD
DOI: 10.1093/bja/aes448
Keywords
acetylcholine; gamma-aminobutyric acid; anaesthetics; dopamine; exocytosis; glutamate; Na+ channels; nerve terminal; neurotransmitter release; norepinephrine
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Funding
- National Institutes of Health [58055]
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Background. Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals. Methods. Nerve terminals from adult male rat brain were prelabelled with [H-3]glutamate and [C-14]GABA (cerebral cortex), [H-3]norepinephrine (hippocampus), [C-14]dopamine (striatum), or [H-3]choline (precursor of [H-3]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system. Results. Isoflurane at clinical concentrations (<0.7 mM; similar to 2 times median anaesthetic concentration) inhibited Na+ channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC50 (SEM)] of glutamate release [0.37 (0.03) mM; P < 0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na+ channel-independent release evoked by elevated K+ was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC50 = 0.59 (0.03) mM]. Conclusions. Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.
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