In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury. Recently, it has been demonstrated that the burst of xanthine oxidase-mediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia. It is not known, however, whether blocking this substrate formation is sufficient to prevent radical generation and functional injury. Therefore, studies were performed in isolated rat hearts in which xanthine oxidase substrate formation was blocked with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), and measurements of contractile function and free radical generation were performed. Chromatographic measurements of the intracellular adenine nucleotide pool showed that preischemic administration of EHNA blocked postischemic hypoxanthine, xanthine, and inosine formation. Electron paramagnetic resonance spin trapping measurements of free radical generation showed that inhibition of adenosine deaminase with EHNA blocked free radical generation and that it also increased the recovery of contractile function by more than 2-fold. Exogenous infusion of hypoxanthine and xanthine totally reversed the protective effects of EHNA. These results demonstrate that blockade of xanthine oxidase substrate formation by adenosine deaminase inhibition can prevent free radical generation and contractile dysfunction in the postischemic heart.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				F. Ichinose, E. S. Buys, T. G. Neilan, E. M. Furutani, J. G. Morgan, D. S. Jassal, A. R. Graveline, R. J. Searles, C. C. Lim, M. Kaneki, et al. Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Prevents Myocardial Dysfunction in Murine Models of Septic Shock Circ. Res., January 5, 2007; 100(1): 130 - 139. [Abstract] [Full Text] [PDF]

				L. Willems, M. E. Reichelt, J. G. Molina, C.-X. Sun, J. L. Chunn, K. J. Ashton, J. Schnermann, M. R. Blackburn, and J. P. Headrick Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts Cardiovasc Res, July 1, 2006; 71(1): 79 - 87. [Abstract] [Full Text] [PDF]

				J. L. Zweier and M.A. H. Talukder The role of oxidants and free radicals in reperfusion injury Cardiovasc Res, May 1, 2006; 70(2): 181 - 190. [Abstract] [Full Text] [PDF]

				A. Tapodi, B. Debreceni, K. Hanto, Z. Bognar, I. Wittmann, F. Gallyas Jr., G. Varbiro, and B. Sumegi Pivotal Role of Akt Activation in Mitochondrial Protection and Cell Survival by Poly(ADP-ribose)polymerase-1 Inhibition in Oxidative Stress J. Biol. Chem., October 21, 2005; 280(42): 35767 - 35775. [Abstract] [Full Text] [PDF]

				G. Paradies, G. Petrosillo, M. Pistolese, N. Di Venosa, A. Federici, and F. M. Ruggiero Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart: Involvement of Reactive Oxygen Species and Cardiolipin Circ. Res., January 9, 2004; 94(1): 53 - 59. [Abstract] [Full Text] [PDF]

				J. P. Headrick, B. Hack, and K. J. Ashton Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1797 - H1818. [Abstract] [Full Text] [PDF]

				S. C Tjen-A-Looi, L.-W. Fu, and J. C Longhurst Xanthine oxidase, but not neutrophils, contributes to activation of cardiac sympathetic afferents during myocardial ischaemia in cats J. Physiol., August 15, 2002; 543(1): 327 - 336. [Abstract] [Full Text] [PDF]

				J. Fukuzawa, J. Nishihira, N. Hasebe, T. Haneda, J. Osaki, T. Saito, T. Nomura, T. Fujino, N. Wakamiya, and K. Kikuchi Contribution of Macrophage Migration Inhibitory Factor to Extracellular Signal-regulated Kinase Activation by Oxidative Stress in Cardiomyocytes J. Biol. Chem., July 5, 2002; 277(28): 24889 - 24895. [Abstract] [Full Text] [PDF]

				W. Huber, K. Ilgmann, M. Page, M. Hennig, U. Schweigart, B. Jeschke, L. Lutilsky, W. Weiss, H. Salmhofer, and M. Classen Effect of Theophylline on Contrast Material-induced Nephropathy in Patients with Chronic Renal Insufficiency: Controlled, Randomized, Double-blinded Study Radiology, June 1, 2002; 223(3): 772 - 779. [Abstract] [Full Text] [PDF]

				J. Peart, G. Paul Matherne, R. J. Cerniway, and J. P. Headrick Cardioprotection with adenosine metabolism inhibitors in ischemic-reperfused mouse heart Cardiovasc Res, October 1, 2001; 52(1): 120 - 129. [Abstract] [Full Text] [PDF]

				Y. Xia, A.-L. Tsai, V. Berka, and J. L. Zweier Superoxide Generation from Endothelial Nitric-oxide Synthase. A Ca2+/CALMODULIN-DEPENDENT AND TETRAHYDROBIOPTERIN REGULATORY PROCESS J. Biol. Chem., October 2, 1998; 273(40): 25804 - 25808. [Abstract] [Full Text] [PDF]

				Y. Xia, L. J. Roman, B. S. S. Masters, and J. L. Zweier Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain J. Biol. Chem., August 28, 1998; 273(35): 22635 - 22639. [Abstract] [Full Text] [PDF]

				N. G. Perez, W. D. Gao, and E. Marban Novel Myofilament Ca2+-Sensitizing Property of Xanthine Oxidase Inhibitors Circ. Res., August 24, 1998; 83(4): 423 - 430. [Abstract] [Full Text] [PDF]

				D. T. Lucas and L. I. Szweda Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction PNAS, January 20, 1998; 95(2): 510 - 514. [Abstract] [Full Text] [PDF]

				J. Barankiewicz, A. M. Danks, E. Abushanab, L. Makings, T. Wiemann, R. A. Wallis, P. V. P. Pragnacharyulu, A. Fox, and P. J. Marangos Regulation of Adenosine Concentration and Cytoprotective Effects of Novel Reversible Adenosine Deaminase Inhibitors J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1230 - 1238. [Abstract] [Full Text]