title: Sevoflurane exposure generates superoxide but leads to decreased superoxide during ischemia and reperfusion in isolated hearts.
abstract: Reactive oxygen species (ROS) are largely responsible for cardiac injury consequent to ischemia and reperfusion, but, paradoxically, there is evidence suggesting that anesthetics induce preconditioning (APC) by generating ROS. We hypothesized that sevoflurane generates the ROS superoxide (O(2)(.-)), that APC attenuates O(2)(.-) formation during ischemia, and that this attenuation is reversed by bracketing APC with the O(2)(.-) scavenger manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the putative mitochondrial adenosine triphosphate-sensitive potassium (mK(ATP)) channel blocker 5-hydroxydecanoate (5-HD). O(2)(.-) was measured continuously in guinea pig hearts by using dihydroethidium. Sevoflurane was administered alone (APC), with MnTBAP, or with 5-HD before 30 min of ischemia and 120 min of reperfusion. Control hearts underwent no pretreatment. Sevoflurane directly increased O(2)(.-); this was blocked by MnTBAP but not by 5-HD. O(2)(.-) increased during ischemia and during reperfusion. These increases in O(2)(.-) were attenuated in the APC group, but this was prevented by MnTBAP or 5-HD. We conclude that sevoflurane directly induces O(2)(.-) formation but that O(2)(.-) formation is decreased during subsequent ischemia and reperfusion. The former effect appears independent of mK(ATP) channels, but not the latter. Our study indicates that APC is initiated by ROS that in turn cause mK(ATP) channel opening. Although there appears to be a paradoxical role for ROS in triggering and mediating APC, a possible mechanism is offered.
  
  
  CONCLUSIONS
  Reactive oxygen species (ROS) are implicated in triggering anesthetic preconditioning (APC). The ROS superoxide (O(2)(.-)) was measured continuously in guinea pig isolated hearts. Sevoflurane directly increased O(2)(.-) but led to attenuated O(2)(.-) formation during ischemia. This demonstrates triggering of APC by ROS and clarifies the mechanism of cardioprotection during ischemia.
authors.affiliation: Anesthesiology Research Laboratories, Departments of *Anesthesiology and †Physiology, and §Cardiovascular Research Center, The Medical College of Wisconsin, Milwaukee, Wisconsin; ‡Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; and ∥Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin.
authors.forename: Leo G
authors.initials: LG
authors.lastname: Kevin
authors.forename: Enis
authors.initials: E
authors.lastname: Novalija
authors.forename: Matthias L
authors.initials: ML
authors.lastname: Riess
authors.forename: Amadou K S
authors.initials: AKS
authors.lastname: Camara
authors.forename: Samhita S
authors.initials: SS
authors.lastname: Rhodes
authors.forename: David F
authors.initials: DF
authors.lastname: Stowe
mesh_terms: D018528:ATP-Binding Cassette Transporters; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D004996:Ethidium / Q000031:analogs & derivatives*; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels; D008738:Methyl Ethers / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077149:Sevoflurane; D013050:Spectrometry, Fluorescence; D013481:Superoxides / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D018685:Anesthetics, Inhalation; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D054086:KATP Channels; D008738:Methyl Ethers; D016877:Oxidants; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; C092520:uK-ATP-1 potassium channel; C067883:dihydroethidium; D013481:Superoxides; D000077149:Sevoflurane; D004996:Ethidium; D002118:Calcium