Circulation Research, Vol 66, 913-931, Copyright © 1990 by American Heart Association

ARTICLES

Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode

CE Murry, VJ Richard, KA Reimer and RB Jennings
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.

We have shown previously that preconditioning myocardium with four 5- minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or 40 minutes of sustained ischemia. All groups had comparable collateral blood flow. Preconditioned hearts developed ultrastructural injury more slowly than controls; evidence of irreversible injury was observed after 20 minutes in controls but not until 40 minutes in preconditioned hearts. Furthermore, after 40 minutes of ischemia, irreversible injury was homogeneous in controls but only focal in preconditioned myocardium. Preconditioning reduced starting levels of ATP by 29%. Nevertheless, it also slowed the rate of ATP depletion during the episode of sustained ischemia, so that after 10 minutes of ischemia, preconditioned hearts had more ATP than controls. However, after 40 minutes, ATP contents were not significantly different between groups. Preservation of ATP resulted from reduced ATP utilization and was not due to increased ATP production. Accumulation of purine nucleosides and bases (products of adenine nucleotide degradation) was limited in preconditioned myocardium. Accumulation of glucose-1-phosphate, glucose-6-phosphate, and lactate also was reduced markedly by preconditioning, due to reduced rates of glycogen breakdown and and anaerobic glycolysis. We propose that preconditioning reduces myocardial energy demand during ischemia, which results in a reduced rate of high energy phosphate utilization and a reduced rate of anaerobic glycolysis. Either preservation of ATP or reduction of the cellular load of catabolites may be responsible for delaying ischemic cell death.

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				Y. Takasaki, N. Adachi, K. Dote, S. Tsubota, T. Yorozuya, and T. Arai Ischemic preconditioning suppresses the noradrenaline turnover in the rat heart Cardiovasc Res, August 1, 1998; 39(2): 373 - 380. [Abstract] [Full Text] [PDF]

				R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]

				M. Arai, S. Minatoguchi, G. Takemura, Y. Uno, T. Kariya, H. Takatsu, T. Fujiwara, M. Higashioka, Y. Yoshikuni, and H. Fujiwara N-Methyl-1-Deoxynojirimycin (MOR-14), an {alpha}-Glucosidase Inhibitor, Markedly Reduced Infarct Size in Rabbit Hearts Circulation, April 7, 1998; 97(13): 1290 - 1297. [Abstract] [Full Text] [PDF]

				R. J. Domenech, P. Macho, D. Velez, G. Sanchez, X. Liu, and N. Dhalla Tachycardia Preconditions Infarct Size in Dogs : Role of Adenosine and Protein Kinase C Circulation, March 3, 1998; 97(8): 786 - 794. [Abstract] [Full Text] [PDF]

				L. A. Gustafson and K. Kroll Downregulation of 5'-nucleotidase in rabbit heart during coronary underperfusion Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H529 - H538. [Abstract] [Full Text] [PDF]

				T. Shirai, V. Rao, R. D. Weisel, J. S. Ikonomidis, R.-K. Li, L. C. Tumiati, F. Merante, and D. A. Mickle Preconditioning human cardiomyocytes and endothelial cells J. Thorac. Cardiovasc. Surg., January 1, 1998; 115(1): 210 - 214. [Abstract] [Full Text] [PDF]

				D. W. Green, H. N. Murray, P. G. Sleph, F.-L. Wang, A. J. Baird, W. L. Rogers, and G. J. Grover Preconditioning in rat hearts is independent of mitochondrial F1F0 ATPase inhibition Am J Physiol Heart Circ Physiol, January 1, 1998; 274(1): H90 - H97. [Abstract] [Full Text] [PDF]

				L. R.C Dekker Toward the heart of ischemic preconditioning Cardiovasc Res, January 1, 1998; 37(1): 14 - 20. [Full Text] [PDF]

				L. P. Perrault, P. Menasche, K. V. Ylitalo, and K. J. Peuhkurinen Ischemic Preconditioning Before Normothermic Retrograde Cardioplegia Ann. Thorac. Surg., December 1, 1997; 64(6): 1874 - 1876. [Full Text]

				A. C. Cave, A. S. Silverman, and C. S. Apstein Ischemic Preconditioning Does Not Protect Against Contractile Dysfunction in the Presence of Residual Flow : Studies in the Isolated, Blood-Perfused Rat Heart Circulation, November 4, 1997; 96(9): 3087 - 3093. [Abstract] [Full Text]

				S. A. Gabel, H. R. Cross, R. E. London, C. Steenbergen, and E. Murphy Decreased intracellular pH is not due to increased H+ extrusion in preconditioned rat hearts Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2257 - H2262. [Abstract] [Full Text] [PDF]

				T. Oxman, M. Arad, R. Klein, N. Avazov, and B. Rabinowitz Limb ischemia preconditions the heart against reperfusion tachyarrhythmia Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1707 - H1712. [Abstract] [Full Text] [PDF]

				C. S Carr, R. J Hill, H. Masamune, S. P Kennedy, D. R Knight, W.R. Tracey, and D. M Yellon Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia Cardiovasc Res, October 1, 1997; 36(1): 52 - 59. [Abstract] [Full Text] [PDF]

				H. Miyawaki and M. Ashraf Ca2+ as a Mediator of Ischemic Preconditioning Circ. Res., June 19, 1997; 80(6): 790 - 799. [Abstract] [Full Text]

				P. K. Kaukoranta, M. P. K. Lepojarvi, K. V. Ylitalo, K. T. Kiviluoma, and K. J. Peuhkurinen Normothermic Retrograde Blood Cardioplegia With or Without Preceding Ischemic Preconditioning Ann. Thorac. Surg., May 1, 1997; 63(5): 1268 - 1274. [Abstract] [Full Text]

				K.-i. Yabe, Y. Nasa, M. Sato, R. Iijima, and S. Takeo Preconditioning preserves mitochondrial function and glycolytic flux during an early period of reperfusion in perfused rat hearts Cardiovasc Res, March 1, 1997; 33(3): 677 - 685. [Abstract] [PDF]