Mitochondrial adenosine triphosphate-regulated potassium channel opening acts as a trigger for isoflurane-induced preconditioning by generating reactive oxygen species

• Published in: Anesthesiology (Philadelphia) 2003-04, Vol.98 (4), p.935-943
• Main Authors: TANAKA, Katsuya, WEIHRAUCH, Dorothee, LUDWIG, Lynda M, KERSTEN, Judy R, PAGEL, Paul S, WARLTIER, David C
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - physiology; Anesthetics, Inhalation - pharmacology; Anesthetics. Neuromuscular blocking agents; Animals; Biological and medical sciences; Ethidium; Fluorescent Dyes; Free Radical Scavengers - pharmacology; Hemodynamics - drug effects; Hemodynamics - physiology; Ion Channel Gating - physiology; Ischemic Preconditioning, Myocardial; Isoflurane - pharmacology; Male; Medical sciences; Microscopy, Confocal; Mitochondria, Heart - enzymology; Mitochondria, Heart - physiology; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - pathology; Neuropharmacology; Pharmacology. Drug treatments; Potassium Channels - physiology; Pulmonary Alveoli - metabolism; Rabbits; Reactive Oxygen Species - metabolism
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-200304000-00021

Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo. Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent. The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.