title: The cardioprotectant 3',4'-dihydroxyflavonol inhibits opening of the mitochondrial permeability transition pore after myocardial ischemia and reperfusion in rats.
abstract: The study aimed to determine the effect of 3',4'-dihydroxyflavonol (DiOHF) on mitochondrial function, in particular opening of the mitochondrial permeability transition pore (mPTP), respiratory function and reactive oxygen species (ROS) production, in isolated cardiac mitochondria after coronary artery occlusion and reperfusion in vivo. Opening of the mPTP, oxygen consumption and ROS production (assessed by measurement of H2O2) was determined in mitochondria isolated from normal hearts or from the ischemic zone of rat hearts subjected to 30min coronary artery occlusion and 15min reperfusion. Treatment of sham rats with DiOHF (10mgkg(-1) iv) significantly increased the concentration of Ca(2+) required to stimulate mPTP opening. This was accompanied by increased state 3 oxygen consumption and decreased H2O2 release. Ischemia and reperfusion (IR) significantly decreased the concentration of Ca(2+) required to stimulate mPTP opening, decreased state 3 oxygen consumption and increased H2O2 release, when pyruvate plus malate was provided as a substrate. Treatment with DiOHF prevented IR-induced changes in mPTP opening, state 3 oxygen consumption and H2O2 release so that there was no difference compared to sham. In isolated cardiac mitochondria from normal rats DiOHF had no effect on mPTP opening or on state 3 respiration but caused a small increase in state 4 respiration and decreased the respiratory control ratio. DiOHF, administered during ischemia just before reperfusion, inhibits mPTP opening and preserves mitochondrial function through a mechanism likely to be independent of its antioxidant activity or any direct effect on the mPTP.
authors: School of Medical Sciences, Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia. Electronic address: owen.woodman@rmit.edu.au.
authors: O L
authors: OL
authors: Woodman
authors: INSERM U955, Equipe 3, Créteil Cedex 94000, France; University Paris Est, Faculté de Médecine, Créteil 94000, France.
authors: R
authors: R
authors: Long
authors: INSERM U955, Equipe 3, Créteil Cedex 94000, France; University Paris Est, Faculté de Médecine, Créteil 94000, France.
authors: S
authors: S
authors: Pons
authors: INSERM U955, Equipe 3, Créteil Cedex 94000, France; University Paris Est, Faculté de Médecine, Créteil 94000, France.
authors: N
authors: N
authors: Eychenne
authors: INSERM U955, Equipe 3, Créteil Cedex 94000, France; University Paris Est, Faculté de Médecine, Créteil 94000, France.
authors: A
authors: A
authors: Berdeaux
authors: INSERM U955, Equipe 3, Créteil Cedex 94000, France; University Paris Est, Faculté de Médecine, Créteil 94000, France.
authors: D
authors: D
authors: Morin
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D044948:Flavonols / Q000494:pharmacology*; D008293:Malates / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D019289:Pyruvic Acid / Q000494:pharmacology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D044948:Flavonols; D008293:Malates; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D012402:Rotenone; C030298:malic acid; D019289:Pyruvic Acid; D019802:Succinic Acid; C529890:3',4'-dihydroxyflavonol
keywords: 3′,4′-Dihydroxyflavonol; Cardiac ischemia and reperfusion; Mitochondrial permeability transition pore (mPTP); Mitochondrial respiration; Reactive oxygen species