Sevoflurane depolarizes pre-synaptic mitochondria in the central nervous system
Volatile anaesthetics protect the heart from ischaemic injury by activating mitochondrial signalling pathways. The aim of this study was to test whether sevoflurane, which is increasingly used in neuroanaesthesia, affects mitochondrial function in the central nervous system by altering the mitochondrial membrane potential (ΔΨm). Methods:
In order to correlate free cytosolic Ca2+ ([Ca2+]i) and ΔΨm, rat neural presynaptic terminals (synaptosomes) were loaded with the fluorescent probes fura-2 and JC-1. During sevoflurane exposure, 4-aminopyridine (4-AP) 500 µM to induce pre-synaptic membrane depolarization or carbonylcyanide-p-(trifluoromethoxy)-phenylhydrazone (FCCP) 1 µM to induce maximum mitochondrial depolarization was added. In order to block mitochondrial ATP-regulated K+-channels (mitoKATP), the antagonist 5-hydroxydecanoate (5-HD) 500 µM was added. Results:
In Ca2+-containing medium, both sevoflurane 1 and 2 MAC gradually decreased the normalized JC-1 ratio from 0.96 ± 0.01 in control to 0.92 ± 0.01 and 0.89 ± 0.01, representing a depolarization of ΔΨm (n = 9, P < 0.05). Sevoflurane 2 MAC increased [Ca2+]i. In Ca2+-depleted medium, sevoflurane 1 and 2 MAC depolarized ΔΨm, while [Ca2+]i remained unaltered. Sevoflurane 2 MAC attenuated the 4-AP-induced depolarization of ΔΨm. When mitoKATP was blocked, the sevoflurane-induced depolarization of ΔΨm was attenuated, but not blocked. The depolarizing effect of sevoflurane on ΔΨm compared with FCCP was calculated to 13.2 ± 1.3% in Ca2+-containing and 15.1 ± 1.2% in Ca2+-depleted medium (n = 7). Conclusions:
Sevoflurane depolarizes ΔΨm in rat synaptosomes, and the effect is not dependent on Ca2+-influx to the cytosol. Opening of mitoKATP is partly responsible for the depolarizing effect of sevoflurane.
Document Type: Research Article
Affiliations: Institute for Surgical Research and Department of Neurosurgery, Rikshospitalet University Hospital, 0027 Oslo, Norway
Publication date: 2004-05-01