© 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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Z. Xu, X. Ji, and P. G. Boysen Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1433 - H1440. [Abstract] [Full Text] [PDF]
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B. O'Rourke Evidence for Mitochondrial K+ Channels and Their Role in Cardioprotection Circ. Res., March 5, 2004; 94(4): 420 - 432. [Abstract] [Full Text] [PDF]
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M. Canton, I. Neverova, R. Menabo, J. Van Eyk, and F. Di Lisa Evidence of myofibrillar protein oxidation induced by postischemic reperfusion in isolated rat hearts Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H870 - H877. [Abstract] [Full Text] [PDF]
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B. N. Eigel, H. Gursahani, and R. W. Hadley ROS are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H955 - H963. [Abstract] [Full Text] [PDF]
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A. P Halestrap, S. J Clarke, and S. A Javadov Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 372 - 385. [Abstract] [Full Text] [PDF]
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M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]
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E. Murphy Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection Circ. Res., January 9, 2004; 94(1): 7 - 16. [Abstract] [Full Text] [PDF]
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T. Miura, Y. Ohnuma, A. Kuno, M. Tanno, Y. Ichikawa, Y. Nakamura, T. Yano, T. Miki, J. Sakamoto, and K. Shimamoto Protective role of gap junctions in preconditioning against myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H214 - H221. [Abstract] [Full Text] [PDF]
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O. Oldenburg, Q. Qin, T. Krieg, X.-M. Yang, S. Philipp, S. D. Critz, M. V. Cohen, and J. M. Downey Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H468 - H476. [Abstract] [Full Text] [PDF]
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W. de Ruijter, R. J.P. Musters, C. Boer, G. J. M. Stienen, W. S. Simonides, and J. J. de Lange The Cardioprotective Effect of Sevoflurane Depends on Protein Kinase C Activation, Opening of Mitochondrial K+ATP Channels, and the Production of Reactive Oxygen Species Anesth. Analg., November 1, 2003; 97(5): 1370 - 1376. [Abstract] [Full Text] [PDF]
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M. Zaugg, E. Lucchinetti, M. Uecker, T. Pasch, and M. C. Schaub Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms Br. J. Anaesth., October 1, 2003; 91(4): 551 - 565. [Abstract] [Full Text] [PDF]
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D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
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 J. F. Huizar, L. A. Gonzalez, J. Alderman, and H. S. Smith Sulfonylureas attenuate electrocardiographic ST-segment elevation during an acute myocardial infarction in diabetics J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1017 - 1021. [Abstract] [Full Text] [PDF]
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J. N. Weiss, P. Korge, H. M. Honda, and P. Ping Role of the Mitochondrial Permeability Transition in Myocardial Disease Circ. Res., August 22, 2003; 93(4): 292 - 301. [Abstract] [Full Text] [PDF]
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G. J. Gross and J. N. Peart KATP channels and myocardial preconditioning: an update Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H921 - H930. [Abstract] [Full Text] [PDF]
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 S. Ghosh and M. Galinanes Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 133 - 142. [Abstract] [Full Text] [PDF]
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Y. Uchiyama, H. Otani, T. Okada, T. Uchiyama, H. Ninomiya, M. Kido, H. Imamura, S. Nakao, and K. Shingu Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 148 - 159. [Abstract] [Full Text] [PDF]
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P. Korge, H. M. Honda, and J. N. Weiss Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H259 - H269. [Abstract] [Full Text] [PDF]
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M. M. da Silva, A. Sartori, E. Belisle, and A. J. Kowaltowski Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2 release, and enhances K+ transport Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H154 - H162. [Abstract] [Full Text] [PDF]
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J. Peart and J. P Headrick Adenosine-mediated early preconditioning in mouse: protective signaling and concentration dependent effects Cardiovasc Res, June 1, 2003; 58(3): 589 - 601. [Abstract] [Full Text] [PDF]
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Y. Nakae, W.-M. Kwok, Z. J. Bosnjak, and M. T. Jiang Isoflurane activates rat mitochondrial ATP-sensitive K+ channels reconstituted in lipid bilayers Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1865 - H1871. [Abstract] [Full Text] [PDF]
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S. B. Digerness, P. S. Brookes, S. P. Goldberg, C. R. Katholi, and W. L. Holman Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., April 1, 2003; 125(4): 863 - 871. [Abstract] [Full Text] [PDF]
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T. Krieg, M. Landsberger, M. F. Alexeyev, S. B. Felix, M. V. Cohen, and J. M. Downey Activation of Akt is essential for acetylcholine to trigger generation of oxygen free radicals Cardiovasc Res, April 1, 2003; 58(1): 196 - 202. [Abstract] [Full Text] [PDF]
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 M. Das, J. E Parker, and A. P Halestrap Matrix volume measurements challenge the existence of diazoxide/glibencamide-sensitive KATP channels in rat mitochondria J. Physiol., March 15, 2003; 547(3): 893 - 902. [Abstract] [Full Text] [PDF]
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J. D. McCully and S. Levitsky The mitochondrial KATP channel and cardioprotection Ann. Thorac. Surg., February 1, 2003; 75(2): S667 - 673. [Abstract] [Full Text] [PDF]
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J. Levraut, H. Iwase, Z.-H. Shao, T. L. Vanden Hoek, and P. T. Schumacker Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H549 - H558. [Abstract] [Full Text] [PDF]
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L. G. Kevin, A. K. S. Camara, M. L. Riess, E. Novalija, and D. F. Stowe Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H566 - H574. [Abstract] [Full Text] [PDF]
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