Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain.
BACKGROUND
The mitochondrial membrane potential (DeltaPsim) controls the generation of adenosine triphosphate (ATP) and reactive oxygen species, and sequesteration of intracellular Ca2+[Ca2+]i. Clinical concentrations of sevoflurane affect the DeltaPsim in neural mitochondria, but the mechanisms remain elusive. The aim of the present study was to compare the effect of isoflurane and sevoflurane on DeltaPsim in rat pre-synaptic terminals (synaptosomes), and to investigate whether these agents affect DeltaPsim by inhibiting the respiratory chain.


METHODS
Synaptosomes were loaded with the fluorescent probes JC-1 (DeltaPsim) and Fura-2 ([Ca2+]i) and exposed to isoflurane or sevoflurane. The effect of the anaesthetics on the electron transport chain was investigated by blocking complex I and complex V.


RESULTS
Isoflurane 1 and 2 minimum alveolar concentration (MAC) decreased the normalized JC-1 ratio from 0.92 +/- 0.03 in control to 0.86 +/- 0.02 and 0.81 +/- 0.01, respectively, reflecting a depolarization of the mitochondrial membrane (n = 9). Isoflurane 2 MAC increased [Ca2+]i. In Ca2+-depleted medium, isoflurane still decreased DeltaPsim while [Ca2+]i remained unaltered. The effect of isoflurane was more pronounced than for sevoflurane. Blocking complex V of the respiratory chain enhanced the isoflurane- and sevoflurane-induced mitochondrial depolarization, whereas blocking complex I and V decreased DeltaPsim to the same extent in control, isoflurane and sevoflurane experiments.


CONCLUSIONS
Isoflurane and sevoflurane may act as metabolic inhibitors by depolarizing pre-synaptic mitochondria through inhibition of the electron transport chain, although isoflurane seems to inhibit mitochondrial function more significantly than sevoflurane. Both agents inhibit the respiratory chain sufficiently to cause ATP synthase reversal.
Bains
R
R
Institute for Surgical Research and Department of Neurosurgery, Rikshospitalet University Hospital, Oslo, Norway. r.s.bains@klinmed.uio.no
Moe
M C
MC
Larsen
G A
GA
Berg-Johnsen
J
J
Vinje
M L
ML
D000255:Adenosine Triphosphate / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D004579:Electron Transport / Q000187:drug effects*; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008738:Methyl Ethers / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects*; D017729:Presynaptic Terminals / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D000077149:Sevoflurane; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D018685:Anesthetics, Inhalation; D005456:Fluorescent Dyes; D008738:Methyl Ethers; D000077149:Sevoflurane; D000255:Adenosine Triphosphate; D007530:Isoflurane; D002118:Calcium