title: Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane.
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.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: R I
authors.initials: RI
authors.lastname: Westphalen
authors.forename: K M
authors.initials: KM
authors.lastname: Desai
authors.forename: H C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000378:metabolism; D000077149:Sevoflurane; D013268:Stimulation, Chemical; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; D017661:Receptors, Presynaptic; D000077149:Sevoflurane; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D015761:4-Aminopyridine; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine