Faculty Collaboration Database

Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning. Anesthesiology 2011 Sep;115(3):531-40

Date

08/25/2011

Pubmed ID

21862887

Pubmed Central ID

PMC3337729

DOI

10.1097/ALN.0b013e31822a2316

Scopus ID

2-s2.0-80052165081 (requires institutional sign-in at Scopus site)   64 Citations

Abstract

BACKGROUND: Reactive oxygen species (ROS) mediate the effects of anesthetic precondition to protect against ischemia and reperfusion injury, but the mechanisms of ROS generation remain unclear. In this study, the authors investigated if mitochondria-targeted antioxidant (mitotempol) abolishes the cardioprotective effects of anesthetic preconditioning. Further, the authors investigated the mechanism by which isoflurane alters ROS generation in isolated mitochondria and submitochondrial particles.

METHODS: Rats were pretreated with 0.9% saline, 3.0 mg/kg mitotempol in the absence or presence of 30 min exposure to isoflurane. Myocardial infarction was induced by left anterior descending artery occlusion for 30 min followed by reperfusion for 2 h and infarct size measurements. Mitochondrial ROS production was determined spectrofluorometrically. The effect of isoflurane on enzymatic activity of mitochondrial respiratory complexes was also determined.

RESULTS: Isoflurane reduced myocardial infarct size (40 ± 9% = mean ± SD) compared with control experiments (60 ± 4%). Mitotempol abolished the cardioprotective effects of anesthetic preconditioning (60 ± 9%). Isoflurane enhanced ROS generation in submitochondrial particles with nicotinamide adenine dinucleotide (reduced form), but not with succinate, as substrate. In intact mitochondria, isoflurane enhanced ROS production in the presence of rotenone, antimycin A, or ubiquinone when pyruvate and malate were substrates, but isoflurane attenuated ROS production when succinate was substrate. Mitochondrial respiratory experiments and electron transport chain complex assays revealed that isoflurane inhibited only complex I activity.

CONCLUSIONS: The results demonstrated that isoflurane produces ROS at complex I and III of the respiratory chain via the attenuation of complex I activity. The action on complex I decreases unfavorable reverse electron flow and ROS release in myocardium during reperfusion.

Author List

Hirata N, Shim YH, Pravdic D, Lohr NL, Pratt PF Jr, Weihrauch D, Kersten JR, Warltier DC, Bosnjak ZJ, Bienengraeber M

Author

Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anesthetics, Inhalation
Animals
Cyclic N-Oxides
Electron Transport
Electron Transport Complex I
Electron Transport Complex II
Electron Transport Complex III
Electron Transport Complex IV
Hemodynamics
In Vitro Techniques
Ischemic Preconditioning, Myocardial
Isoflurane
Male
Mitochondria, Heart
Myocardial Infarction
Myocardial Reperfusion
Oxygen Consumption
Rats
Rats, Wistar
Reactive Oxygen Species
Rotenone
Spin Labels
Superoxide Dismutase
Uncoupling Agents