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Mitochondrial K-ATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation

Carroll, R; Gant, VA; Yellon, DM; (2001) Mitochondrial K-ATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation. CARDIOVASC RES , 51 (4) 691 - 700.

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Abstract

Objectives: The mechanism by which the mitochondrial K-ATP 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 K-ATP 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 mitoK(ATP) 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 mitoK(ATP) channel opener diazoxide can act as a trigger of preconditioning by a mechanism involving mitochondrial swelling and the generation of ROS. (C) 2001 Elsevier Science B.V. All rights reserved.

Type:Article
Title:Mitochondrial K-ATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation
Keywords:mitochondria, K-ATP channel, free radicals, preconditioning, HEART-MITOCHONDRIA, CARDIAC MYOCYTES, LIGHT-SCATTERING, OXYGEN RADICALS, MATRIX VOLUME, INTACT-CELLS, 2ND WINDOW, MEMBRANE, JC-1, CARDIOPROTECTION
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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