© 2000 American Heart Association, Inc.
Integrative Physiology |
Opening of Mitochondrial KATP Channels Triggers the Preconditioned State by Generating Free Radicals
From the Departments of Physiology (T.P., X.-M.Y., A.N., G.S.L., G.H., M.V.C., J.M.D.), Cell Biology and Neuroscience (S.D.C., Y.Y.), and Medicine (M.V.C.), College of Medicine, University of South Alabama, Mobile, Ala, and Department of Pathophysiology (G.H.), University of Essen Medical School, Essen, Germany.
Correspondence to James M. Downey, PhD, MSB 3024, Department of Physiology, College of Medicine, University of South Alabama, Mobile, AL 36688.
Abstract—The critical time for opening mitochondrial (mito) KATP channels, putative end effectors of ischemic preconditioning (PC), was examined. In isolated rabbit hearts 29±3% of risk zone infarcted after 30 minutes of regional ischemia. Ischemic PC or 5-minute exposure to 10 µmol/L diazoxide, a mito KATP channel opener, reduced infarction to 3±1% and 8±1%, respectively. The mito KATP channel closer 5-hydroxydecanoate (200 µmol/L), bracketing either 5-minute PC ischemia or diazoxide infusion, blocked protection (24±3 and 28±6% infarction, respectively). However, 5-hydroxydecanoate starting 5 minutes before long ischemia did not affect protection. Glibenclamide (5 µmol/L), another KATP channel closer, blocked the protection by PC only when administered early. These data suggest that KATP channel opening triggers protection but is not the final step. Five minutes of diazoxide followed by a 30-minute washout still reduced infarct size (8±3%), implying memory as seen with other PC triggers. The protection by diazoxide was not blocked by 5 µmol/L chelerythrine, a protein kinase C antagonist, given either to bracket diazoxide infusion or just before the index ischemia. Bracketing preischemic exposure to diazoxide with 50 µmol/L genistein, a tyrosine kinase antagonist, did not affect infarction, but genistein blocked the protection by diazoxide when administered shortly before the index ischemia. Thus, although it is not protein kinase C-dependent, the protection by diazoxide involves tyrosine kinase. Bracketing diazoxide perfusion with N-(2-mercaptopropionyl) glycine (300 µmol/L) or Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (7 µmol/L), each of which is a free radical scavenger, blocked protection, indicating that diazoxide triggers protection through free radicals. Therefore, mito KATP channels are not the end effectors of protection, but rather their opening before ischemia generates free radicals that trigger entrance into a preconditioned state and activation of kinases.
Key Words: diazoxide • 5-hydroxydecanoate • ischemic preconditioning • KATP channels • myocardial infarction
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|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
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|
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|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition Cardiovasc Res, May 1, 2005; 66(2): 222 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Penna, G. Alloatti, S. Cappello, D. Gattullo, G. Berta, B. Mognetti, G. Losano, and P. Pagliaro Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2512 - H2520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kimura, G.-X. Zhang, A. Nishiyama, T. Shokoji, L. Yao, Y.-Y. Fan, M. Rahman, T. Suzuki, H. Maeta, and Y. Abe Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II Hypertension, May 1, 2005; 45(5): 860 - 866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes Triggering Mitochondrial Radical Release: A New Function for NADPH Oxidases Hypertension, May 1, 2005; 45(5): 847 - 848. [Full Text] [PDF]
|
|
|
|
 |
|
 A.-L. Bulteau, K. C. Lundberg, M. Ikeda-Saito, G. Isaya, and L. I. Szweda Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion PNAS, April 26, 2005; 102(17): 5987 - 5991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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