© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Mitochondrial KATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation
aThe Hatter Institute and Centre for Cardiology, University College Hospital and Medical School, Grafton Way, London WC1E 6DB, UK
bThe Department of Medical Microbiology, University College Hospital and Medical School, Grafton Way, London WC1E 6DB, UK
hatter-institute{at}ucl.ac.uk
* Corresponding author. Tel.: +44-203-809-888; fax: +44-203-885-095
Objectives: The mechanism by which the mitochondrial KATP channel openers confer protection against ischemia/reperfusion injury is debated. Evidence suggests that rather than solely being an end effector, opening of these channels may act by a trigger mechanism. We examined the effects of the mitochondrial KATP channel opener, diazoxide on parameters of mitochondrial function with specific reference to reactive oxygen species (ROS) generation in a human atrial derived cell line model of simulated ischemia/reperfusion (LSI/R). Methods and results: Propidium iodide (PI) exclusion was used to assess survival. Diazoxide treatment conferred protection against LSI/R (13.9±0.9% vs. 36.9±4.5% controls) that was abolished by pre-treatment with the mitoKATP channel blocker, 5-hydroxydecanoate (5-HD) (33.3±3.6%) and with the free radical scavenger, 2-mercaptopropionylglycine (MPG) (29±4.0%). Diazoxide caused increased oxidation of the ROS probe, reduced mitotracker orange (1.3 vs. 1.0 arbitrary units for control; P<0.01 vs. control) that was abrogated by either 5-HD or MPG (1.07 and 1.07 arbitrary units, respectively). At the same time there was no change in orange fluorescent signal from the membrane potential sensitive probe, JC-1 indicating no change in mitochondrial membrane potential. Changes in light scattering, reflecting changes in mitochondrial volume, occurred during treatment with diazoxide. Conclusion: These results demonstrate for the first time that the mitoKATP channel opener diazoxide can act as a trigger of preconditioning by a mechanism involving mitochondrial swelling and the generation of ROS.
KEYWORDS Mitochondria; K-ATP channel; Free radicals; Preconditioning
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