Bupivacaine uncouples the mitochondrial oxidative phosphorylation, inhibits respiratory chain complexes I and III and enhances ROS production: results of a study on cell cultures.
This study aimed to validate, in situ, proposed mechanisms of bupivacaine cytotoxicity pointing to impairment of the mitochondrial oxidative metabolism. High resolution oxymetry, carried out on a panel of cell cultures, revealed a dual dose- and time-dependent effect of bupivacaine consisting of uncoupling of the mt Delta mu(H+)-controlled respiratory rates in a cyclosporine A-insensitive manner and further inhibition of the respiratory rates. Intriguingly, a relatively small decrease on the mt Delta Psi (about 20 mV) was sufficient to account for both the bupivacaine- and the FCCP-mediated impairment of the oxidative phosphorylation coupling thereby supporting a common protonophoric mechanism of action. The bupivacaine-induced depression of the cell respiration related to specific inhibition of complexes I and III and accompanied with production of reactive oxygen species. Importantly, inhibition of the respiratory chain complexes was prevented by antioxidant treatment and reversed following removal of the anaesthetic thereby suggesting an oxidant-mediated feed-back mechanism reinforcing the primary inhibitory action of the anaesthetic.
Cela
Olga
O
Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
Piccoli
Claudia
C
Scrima
Rosella
R
Quarato
Giovanni
G
Marolla
Alessandra
A
Cinnella
Gilda
G
Dambrosio
Michele
M
Capitanio
Nazzareno
N
D000818:Animals; D002045:Bupivacaine / Q000633:toxicity*; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014475:Uncoupling Agents / Q000633:toxicity*
D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D002045:Bupivacaine