title: Preconditioning by isoflurane is mediated by reactive oxygen species generated from mitochondrial electron transport chain complex III.
abstract: Reactive oxygen species (ROS) mediate volatile anesthetic preconditioning. We tested the hypothesis that isoflurane (ISO) generates ROS from electron transport chain complexes I and III. Rabbits (n = 55) underwent 30 min coronary artery occlusion followed by 3 h reperfusion and received 0.9% saline, the complex I inhibitor diphenyleneiodonium (DPI; 1.5 mg/kg bolus followed by 1.5 mg/kg over 1 h), or the complex III inhibitor myxothiazol (MYX; 0.1 mg/kg bolus followed by 0.3 mg/kg over 1 h) in the absence and presence of 1.0 minimum alveolar concentration ISO. ISO was administered for 30 min and discontinued 15 min before coronary occlusion. Infarct size and ROS production (n = 32) were determined using triphenyltetrazolium staining and ethidium-DNA fluorescence, respectively. Adenosine triphosphate (ATP) synthesis in mitochondria obtained from rabbit hearts (n = 24) subjected to drug interventions was measured by luciferin-luciferase luminometry. ISO significantly (P < 0.05) reduced infarct size (19% +/- 4%) as compared with control (39% +/- 4%). MYX (35% +/- 4%), but not DPI (24% +/- 2%), abolished this protection. ISO increased ethidium-DNA fluorescence (83 +/- 11 U) as compared with control (40 +/- 12 U). MYX (35 +/- 3 U), but not DPI (78 +/- 9 U), abolished ROS generation. DPI and MYX selectively reduced complex I- and complex III-mediated ATP synthesis, respectively. ROS generated from electron transport chain complex III mediate ISO-induced cardioprotection.
authors.affiliation: Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin and the Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Ludwig
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanaka
authors.forename: Janis T
authors.initials: JT
authors.lastname: Eells
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.forename: Paul S
authors.initials: PS
authors.lastname: Pagel
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
authors.forename: David C
authors.initials: DC
authors.lastname: Warltier
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D003067:Coenzymes; D004579:Electron Transport / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008689:Methacrylates; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D009245:NADH Dehydrogenase / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D003067:Coenzymes; D004791:Enzyme Inhibitors; D008689:Methacrylates; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014451:Ubiquinone; C007517:diphenyleneiodonium; C030517:myxothiazol; D000255:Adenosine Triphosphate; D007530:Isoflurane; D009245:NADH Dehydrogenase; C024989:coenzyme Q10