Minners, J; Lacerda, L; Yellon, DM; Opie, LH; McLeod, CJ; Sack, MN; (2007) Diazoxide-induced respiratory inhibition - a putative mitochondrial K-ATP channel independent mechanism of pharmacological preconditioning. MOL CELL BIOCHEM , 294 (1-2) 11 - 18. 10.1007/s11010-005-9066-6.
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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 K-ATP (mK(ATP)) channel which was originally proposed has been questioned. Here, we present data supporting an alternate hypothesis evoking mitochondrial respiratory inhibition rather than mK(ATP) channel activation, as a mediating event in the diazoxide-activated cytoprotective program. Mitochondrial respiration and reactive oxygen species (ROS) production was measured in digitonin-permeabilized C2C12 myotubes, allowing for the modulation of mK(ATP) conductance by changing the potassium concentration of the medium (0-130 mM). Diazoxide dose-dependently attenuated succinate-supported respiration, an effect that was independent of mK(ATP) channel conductance. Similarly, 5-hydroxydecanoate (5-HD), a putative mK(ATP) channel blocker, released diazoxide-induced respiratory inhibition independently of potassium concentration. Since diazoxide-induced 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 5-HD inhibited ROS production under the same conditions. Collectively these data support the hypothesis that diazoxide-mediated cytoprotection is independent of the conductance of the mK(ATP) channel and rather implicate mitochondrial respiratory inhibition-triggered ROS signaling.
|Title:||Diazoxide-induced respiratory inhibition - a putative mitochondrial K-ATP channel independent mechanism of pharmacological preconditioning|
|Keywords:||diazoxide, 5-hydroxydecanoate, respiratory inhibition, reactive oxygen species, C2C12 cells, anoxia-reoxygenation, SENSITIVE POTASSIUM CHANNELS, OXYGEN SPECIES GENERATION, REACTIVE OXYGEN, NITRIC-OXIDE, RAT-HEART, INDUCED CARDIOPROTECTION, UNCOUPLING PROTEIN-2, SIMULATED ISCHEMIA, HYDROGEN-PEROXIDE, OXIDATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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