Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues.
A substantial body of evidence indicates that pharmacological activation of mitochondrial ATP-sensitive potassium channels (mKATP) in the heart is protective in conditions associated with ischemia/reperfusion injury. Several mechanisms have been postulated to be responsible for cardioprotection, including the modulation of mitochondrial respiratory function. The aim of the present study was to characterize the dose-dependent effects of novel synthetic benzopyran analogues, derived from a BMS-191095, a selective mKATP opener, on mitochondrial respiration and reactive oxygen species (ROS) production in isolated rat heart mitochondria. Mitochondrial respiratory function was assessed by high-resolution respirometry, and H2O2 production was measured by the Amplex Red fluorescence assay. Four compounds, namely KL-1487, KL-1492, KL-1495, and KL-1507, applied in increasing concentrations (50, 75, 100, and 150 μmol/L, respectively) were investigated. When added in the last two concentrations, all compounds significantly increased State 2 and 4 respiratory rates, an effect that was not abolished by 5-hydroxydecanoate (5-HD, 100 μmol/L), the classic mKATP inhibitor. The highest concentration also elicited an important decrease of the oxidative phosphorylation in a K(+) independent manner. Both concentrations of 100 and 150 μmol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 μmol/L for KL-1507, respectively, mitigated the mitochondrial H2O2 release. In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.
a Department of Pathophysiology, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, 14, Tudor Vladimirescu st. 300173 Timisoara, Romania.
Alexandra
A
Petruş
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Oana M
OM
Duicu
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Adrian
A
Sturza
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Lavinia
L
Noveanu
c Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Szeged, Szeged, Hungary.
Loránd
L
Kiss
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Maria
M
Dănilă
a Department of Pathophysiology, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, 14, Tudor Vladimirescu st. 300173 Timisoara, Romania.
István
I
Baczkó
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Danina M
DM
Muntean
b Department of Pathophysiology, Center for Translational Research and Systems Medicine, "Victor Babeş" University of Medicine and Pharmacy of Timişoara, Romania.
Norbert
N
Jost
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects*; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000819:agonists / Q000037:antagonists & inhibitors; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D001578:Benzopyrans; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D017382:Reactive Oxygen Species; C052853:5-hydroxydecanoic acid; D006861:Hydrogen Peroxide
analogues du benzopyrane; benzopyran analogues; effet découplant; hydrogen peroxide; mitochondries du cœur de rat; peroxyde d’hydrogène; protonophores; rat heart mitochondria; uncoupling