Isoflurane inhibits transmitter release and the presynaptic action potential.
BACKGROUND
Isoflurane inhibits the excitatory postsynaptic current (EPSC) at many synapses. Accumulated evidence suggests the involvement of a presynaptic mechanism. However, the extent of the presynaptic contribution has not been quantitatively studied. Furthermore, the mechanism underlying the presynaptic contribution remains unclear.


METHODS
To estimate the presynaptic contribution, the authors compared the effects of isoflurane on the presynaptic capacitance jump, which is proportional to vesicle release, and the postsynaptic glutamate receptor-mediated EPSC at a calyx-type synapse in rat brainstem. The authors determined whether isoflurane affects the waveform of the action potential recorded from nerve terminals. By studying the relation between the EPSC and the presynaptic action potential at the same synapse, the authors determined whether isoflurane inhibits the EPSC by decreasing the presynaptic action potential.


RESULTS
Isoflurane at 0.35-1.05 mM reduced the EPSC and the presynaptic capacitance jump to a similar degree without affecting the miniature EPSC (an indicator of quantal size), suggesting that isoflurane inhibits the EPSC predominantly by reducing glutamate release. Isoflurane reduced the presynaptic action potential by approximately 3-8%. The EPSC was proportional to the presynaptic action potential amplitude raised to a power of 10.2. Based on this relation, inhibition of the presynaptic action potential contributed to 62-78% of isoflurane-induced inhibition of the EPSC.


CONCLUSIONS
Isoflurane inhibits the EPSC predominantly by inhibition of transmitter release. Isoflurane reduces the presynaptic action potential amplitude, which may contribute significantly to its inhibitory effect on the EPSC.
Wu
Xin-Sheng
XS
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA. wu1@ninds.nih.gov
Sun
Jian-Yuan
JY
Evers
Alex S
AS
Crowder
Michael
M
Wu
Ling-Gang
LG
D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000502:physiology; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000378:metabolism*
D018685:Anesthetics, Inhalation; D015220:Calcium Channels; D018377:Neurotransmitter Agents; D017661:Receptors, Presynaptic; D018698:Glutamic Acid; D007530:Isoflurane