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

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 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.

• Authors: Alexandra Petruş, Oana M Duicu, Adrian Sturza, Lavinia Noveanu, Loránd Kiss, Maria Dănilă, István Baczkó, Danina M Muntean, Norbert Jost
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 93 Issue 9 Pg. 811-8 (Sep 2015) ISSN: 1205-7541 [Electronic] Canada
• PMID: 26325241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzopyrans
• Decanoic Acids
• Hydroxy Acids
• KATP Channels
• Reactive Oxygen Species
• 5-hydroxydecanoic acid
• Hydrogen Peroxide

Topics

• Animals
• Benzopyrans (antagonists & inhibitors, chemistry, pharmacology)
• Cell Respiration (drug effects)
• Decanoic Acids (pharmacology)
• Dose-Response Relationship, Drug
• Hydrogen Peroxide (metabolism)
• Hydroxy Acids (pharmacology)
• KATP Channels (agonists, antagonists & inhibitors)
• Male
• Mitochondria, Heart (drug effects, metabolism)
• Molecular Structure
• Oxidative Phosphorylation (drug effects)
• Rats
• Reactive Oxygen Species (metabolism)