Title | Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Westphalen RI, Desai KM, Hemmings HC |
Journal | Br J Anaesth |
Volume | 110 |
Issue | 4 |
Pagination | 592-9 |
Date Published | 2013 Apr |
ISSN | 1471-6771 |
Keywords | 4-Aminopyridine, Acetylcholine, Anesthetics, Inhalation, Animals, Central Nervous System, Dopamine, Dose-Response Relationship, Drug, gamma-Aminobutyric Acid, Glutamic Acid, Male, Methyl Ethers, Neurotransmitter Agents, Norepinephrine, Potassium Channel Blockers, Potassium Chloride, Rats, Rats, Sprague-Dawley, Receptors, Presynaptic, Sevoflurane, Stimulation, Chemical |
Abstract | 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 [(3)H]glutamate and [(14)C]GABA (cerebral cortex), [(3)H]norepinephrine (hippocampus), [(14)C]dopamine (striatum), or [(3)H]choline (precursor of [(3)H]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; ~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 IC(50) (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 [IC(50)=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. |
DOI | 10.1093/bja/aes448 |
Alternate Journal | Br J Anaesth |
PubMed ID | 23213036 |
PubMed Central ID | PMC3600942 |
Grant List | R01 GM058055 / GM / NIGMS NIH HHS / United States GM 58055 / GM / NIGMS NIH HHS / United States |