Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues

Petrus, Alexandra and Duicu, Oana and Sturza, Adrian and Noveanu, Lavinia and Kiss, Loránd and Danila, Maria and Bazckó, István and Muntean, Danina and Jost, Norbert (2015) Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues. CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 93. pp. 811-818. ISSN 0008-4212

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Abstract

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 �mol/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 �mol/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 �mol/L for KL-1487, KL-1492, and KL-1495, and the concentration of 150 �mol/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.

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