© 1997 American Heart Association, Inc.
Articles |
Cardioprotective Effect of Diazoxide and Its Interaction With Mitochondrial ATP-Sensitive K+ Channels
Possible Mechanism of Cardioprotection
From the Department of Chemistry, Biochemistry, and Molecular Biology (K.D.G., P.P., V.Y.-Y.), Oregon Graduate Institute of Science and Technology, Portland, and the Department of Cardiovascular Biochemistry (H.N.M., R.B.D., A.J.D., N.J.L., M.A.S., G.J.G.), Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.
Correspondence to Gary J. Grover, PhD, Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000.
Abstract Previous studies showed a poor correlation between sarcolemmal K+ currents and cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP, making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP with a K1/2 of 0.8 µmol/L while being 1000-fold less potent at opening sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 µmol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. Whole-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K+ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+ flux in this preparation (K1/2 values, 1.1±0.1 and 0.49±0.05 µmol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazoxide-opened mitochondrial KATP. The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KATP.
Key Words: ATP-sensitive K+ channel • mitochondria • heart • myocardial ischemia
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C.J Zuurbier, O Eerbeek, P.T Goedhart, E.A Struys, N.M Verhoeven, C Jakobs, and C Ince Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart Cardiovasc Res, April 1, 2004; 62(1): 145 - 153. [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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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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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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G. C Rodrigo, N. W Davies, and N. B Standen Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism Cardiovasc Res, February 15, 2004; 61(3): 570 - 579. [Abstract] [Full Text] [PDF]
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D. J. Granville, B. Tashakkor, C. Takeuchi, A. B. Gustafsson, C. Huang, M. R. Sayen, P. Wentworth Jr., M. Yeager, and R. A. Gottlieb Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors PNAS, February 3, 2004; 101(5): 1321 - 1326. [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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M. A. Deja, K. S. Golba, M. Kolowca, K. Widenka, J. Biernat, and S. Wos Diazoxide provides protection to human myocardium in vitro that is concentration dependent Ann. Thorac. Surg., January 1, 2004; 77(1): 226 - 232. [Abstract] [Full Text] [PDF]
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D. V. Cancherini, L. G. Trabuco, N. A. Reboucas, and A. J. Kowaltowski ATP-sensitive K+ channels in renal mitochondria Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1291 - F1296. [Abstract] [Full Text]
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Y. Teshima, M. Akao, S. P. Jones, and E. Marban Cariporide (HOE642), a Selective Na+-H+ Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway Circulation, November 4, 2003; 108(18): 2275 - 2281. [Abstract] [Full Text] [PDF]
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A. Schneider, N. Ad, U. Izhar, I. Khaliulin, J. B. Borman, and H. Schwalb Protection of myocardium by cyclosporin A and insulin: in vitro simulated ischemia study in human myocardium Ann. Thorac. Surg., October 1, 2003; 76(4): 1240 - 1245. [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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Y. Nakae, S. Kohro, Q. H. Hogan, and Z. J. Bosnjak Intracellular Mechanism of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel Activation with Isoflurane Anesth. Analg., October 1, 2003; 97(4): 1025 - 1032. [Abstract] [Full Text] [PDF]
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Y. Teshima, M. Akao, S. P. Jones, and E. Marban Uncoupling Protein-2 Overexpression Inhibits Mitochondrial Death Pathway in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 192 - 200. [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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 Y. Teshima, M. Akao, R. A. Li, T. H. Chong, W. A. Baumgartner, M. V. Johnston, and E. Marban Mitochondrial ATP-Sensitive Potassium Channel Activation Protects Cerebellar Granule Neurons From Apoptosis Induced by Oxidative Stress Stroke, July 1, 2003; 34(7): 1796 - 1802. [Abstract] [Full Text] [PDF]
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J. Minners, C. J. McLeod, and M. N. Sack Mitochondrial plasticity in classical ischemic preconditioning--moving beyond the mitochondrial KATP channel Cardiovasc Res, July 1, 2003; 59(1): 1 - 6. [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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 T. Yamauchi, S. Kashii, H. Yasuyoshi, S. Zhang, Y. Honda, and A. Akaike Mitochondrial ATP-Sensitive Potassium Channel: A Novel Site for Neuroprotection Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2750 - 2756. [Abstract] [Full Text] [PDF]
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K. Y. Kim, Y. W. Shin, S.-O. Kim, H. Lim, S.-E. Yoo, and K. W. Hong Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1142 - 1149. [Abstract] [Full Text] [PDF]
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M. Ichinose, H. Yonemochi, T. Sato, and T. Saikawa Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2235 - H2241. [Abstract] [Full Text] [PDF]
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C. P. Baines, C.-X. Song, Y.-T. Zheng, G.-W. Wang, J. Zhang, O.-L. Wang, Y. Guo, R. Bolli, E. M. Cardwell, and P. Ping Protein Kinase C{epsilon} Interacts With and Inhibits the Permeability Transition Pore in Cardiac Mitochondria Circ. Res., May 2, 2003; 92(8): 873 - 880. [Abstract] [Full Text] [PDF]
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T. Steensrud, D. Nordhaug, O.P. Elvenes, C. Korvald, and D.G. Sorlie Superior myocardial protection with nicorandil cardioplegia Eur. J. Cardiothorac. Surg., May 1, 2003; 23(5): 670 - 677. [Abstract] [Full Text] [PDF]
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 Z. Xie and T. Cai Na+-K+-ATPase-Mediated Signal Transduction: From Protein Interaction to Cellular Function Mol. Interv., May 1, 2003; 3(3): 157 - 168. [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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