|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|
|Date Published||2013 Apr|
|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, Stimulation, Chemical|
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.
|Alternate Journal||Br J Anaesth|
|PubMed Central ID||PMC3600942|
|Grant List||GM 58055 / GM / NIGMS NIH HHS / United States |
R01 GM058055 / GM / NIGMS NIH HHS / United States