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Title of Journal: Mol Cell Biochem

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Abbravation: Molecular and Cellular Biochemistry

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Kluwer Academic Publishers-Plenum Publishers

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DOI

10.1016/0011-2275(67)90005-7

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1573-4919

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Diazoxideinduced respiratory inhibition – a putat

Authors: Jan Minners Lydia Lacerda Derek M Yellon Lionel H Opie Christopher J McLeod Michael N Sack
Publish Date: 2006/11/29
Volume: 294, Issue: 1-2, Pages: 11-18
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Abstract

The ischemic preconditioning biological phenomenon has been explored to identify putative pharmacologic agents to mimic this cytoprotective program against cellular ischemic injury Diazoxide administration confers this cytoprotection however whether this is via direct activation of the putative mitochondrial KATP mKATP channel which was originally proposed has been questioned Here we present data supporting an alternate hypothesis evoking mitochondrial respiratory inhibition rather than mKATP channel activation as a mediating event in the diazoxideactivated cytoprotective program Mitochondrial respiration and reactive oxygen species ROS production was measured in digitoninpermeabilized C2C12 myotubes allowing for the modulation of mKATP conductance by changing the potassium concentration of the medium 0–130 mM Diazoxide dosedependently attenuated succinatesupported respiration an effect that was independent of mKATP channel conductance Similarly 5hydroxydecanoate 5HD a putative mKATP channel blocker released diazoxideinduced respiratory inhibition independently of potassium concentration Since diazoxideinduced cytoprotection and respiratory inhibition are both integrally linked to ROS generation we repeated above experiments following ROS generation using DCF fluorescence Cytoprotective doses of diazoxide increased ROS generation independently of potassium concentration and 5HD inhibited ROS production under the same conditions Collectively these data support the hypothesis that diazoxidemediated cytoprotection is independent of the conductance of the mKATP channel and rather implicate mitochondrial respiratory inhibitiontriggered ROS signaling

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