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Department of Biochemistry and Molecular Biology, Oregon Graduate Institute of Science and Technology, Beaverton, Oregon 97006-8921
There is an emerging consensus
that pharmacological opening of the mitochondrial ATP-sensitive
K+ (KATP) channel protects the heart against
ischemia-reperfusion damage; however, there are widely divergent views
on the effects of openers on isolated heart mitochondria. We have
examined the effects of diazoxide and pinacidil on the bioenergetic
properties of rat heart mitochondria. As expected of hydrophobic
compounds, these drugs have toxic, as well as pharmacological, effects
on mitochondria. Both drugs inhibit respiration and increase membrane proton permeability as a function of concentration, causing a decrease
in mitochondrial membrane potential and a consequent decrease in
Ca2+ uptake, but these effects are not caused by opening
mitochondrial KATP channels. In pharmacological doses (<50
µM), both drugs open mitochondrial KATP channels, and
resulting changes in membrane potential and respiration are minimal.
The increased K+ influx associated with mitochondrial
KATP channel opening is ~30
nmol · min
1 · mg1, a very
low rate that will depolarize by only 1-2 mV. However, this
increase in K+ influx causes a significant increase in
matrix volume. The volume increase is sufficient to reverse matrix
contraction caused by oxidative phosphorylation and can be observed
even when respiration is inhibited and the membrane potential is
supported by ATP hydrolysis, conditions expected during ischemia. Thus
opening mitochondrial KATP channels has little direct
effect on respiration, membrane potential, or Ca2+ uptake
but has important effects on matrix and intermembrane space volumes.
myocardial injury; potassium; cardioprotection; ischemia-reperfusion
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P. Dos Santos, A. J. Kowaltowski, M. N. Laclau, S. Seetharaman, P. Paucek, S. Boudina, J.-B. Thambo, L. Tariosse, and K. D. Garlid Mechanisms by which opening the mitochondrial ATP- sensitive K+ channel protects the ischemic heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H284 - H295. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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Y. Chen, J. H. Traverse, J. Zhang, and R. J. Bache Selective blockade of mitochondrial KATP channels does not impair myocardial oxygen consumption Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H738 - H744. [Abstract] [Full Text] [PDF]
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J. D. Molkentin Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis Circ. Res., June 22, 2001; 88(12): 1220 - 1222. [Full Text] [PDF]
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Y. Liu and B. O'Rourke Opening of Mitochondrial KATP Channels Triggers Cardioprotection : Are Reactive Oxygen Species Involved? Circ. Res., April 27, 2001; 88(8): 750 - 752. [Full Text] [PDF]
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 R. Bajgar, S. Seetharaman, A. J. Kowaltowski, K. D. Garlid, and P. Paucek Identification and Properties of a Novel Intracellular (Mitochondrial) ATP-sensitive Potassium Channel in Brain J. Biol. Chem., August 31, 2001; 276(36): 33369 - 33374. [Abstract] [Full Text] [PDF]
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 P. Korge, H. M. Honda, and J. N. Weiss Protection of cardiac mitochondria by diazoxide and protein kinase C: Implications for ischemic preconditioning PNAS, March 5, 2002; 99(5): 3312 - 3317. [Abstract] [Full Text] [PDF]
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M. Akao, A. Ohler, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Inhibit Apoptosis Induced by Oxidative Stress in Cardiac Cells Circ. Res., June 22, 2001; 88(12): 1267 - 1275. [Abstract] [Full Text] [PDF]
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J. Minners, L. Lacerda, J. McCarthy, J. J. Meiring, D. M. Yellon, and M. N. Sack Ischemic and Pharmacological Preconditioning in Girardi Cells and C2C12 Myotubes Induce Mitochondrial Uncoupling Circ. Res., October 26, 2001; 89(9): 787 - 792. [Abstract] [Full Text] [PDF]
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M. Murata, M. Akao, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca2+ Overload During Simulated Ischemia and Reperfusion: Possible Mechanism of Cardioprotection Circ. Res., November 9, 2001; 89(10): 891 - 898. [Abstract] [Full Text] [PDF]
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H. Ishida, Y. Hirota, C. Genka, H. Nakazawa, H. Nakaya, and T. Sato Opening of Mitochondrial KATP Channels Attenuates the Ouabain-Induced Calcium Overload in Mitochondria Circ. Res., November 9, 2001; 89(10): 856 - 858. [Abstract] [Full Text] [PDF]
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