Circulation Research, Vol 74, 817-828, Copyright © 1994 by American Heart Association

ARTICLES

The relative importance of myocardial energy metabolism compared with ischemic contracture in the determination of ischemic injury in isolated perfused rabbit hearts

JL Vanoverschelde, MF Janier and SR Bergmann
Cardiovascular Division, Washington University School of Medicine, St Louis, MO 63110.

The mechanical effects of ischemic contracture may be important in the development of irreversible cellular damage as it increases mechanical stress on sarcolemmal membranes and restricts endocardial perfusion. To assess the relative importance of these mechanical effects compared with decreased energy supply in the development of irreversible injury, the effects of inhibiting ischemic contracture with 2,3-butanedione monoxime (BDM), an agent that disrupts excitation-contraction coupling, were delineated in isovolumically contracting isolated rabbit hearts. Administration of 20 mmol/L BDM in 12 hearts subjected to 60 minutes of low-flow ischemia prevented ischemic contracture (left ventricular end- diastolic pressure [LVEDP], 12 +/- 3 compared with 48 +/- 14 mm Hg in 20 control hearts; P < .001), reduced membrane damage (creatine kinase [CK] release, -54% compared with control hearts; P < .05), and enhanced functional recovery during reperfusion (left ventricular developed pressure [LVDP], 86 +/- 10% of baseline compared with 56 +/- 23% in control hearts; P < .01). These observations were not related to increased intracavitary pressure and its effects on flow distribution, since venting the left ventricle in additional hearts did not result in improved function during reperfusion. Although it would be tempting to conclude that BDM protected ischemic myocardium by preventing ischemic contracture, administration of BDM was also associated with reduced depletion of ATP during ischemia, perhaps related to diminished energy demand. To distinguish between the relative importance of inhibiting contracture from provision of adequate energy, the period of ischemia was extended to 120 minutes. BDM still prevented ischemic contracture (LVEDP, 10 +/- 6 mm Hg) and preserved ATP stores, but it did not prevent membrane damage (CK release, 483 +/- 254 U/g dry weight) or contractile failure during reperfusion (LVDP, 68 +/- 7% of baseline). In contrast, increasing the rate of anaerobic glycolysis during ischemia by doubling glucose and insulin in the presence of BDM markedly decreased membrane damage (CK release, 114 +/- 72 U/g dry weight; P < .05) and contractile failure during reperfusion (LVDP, 88 +/- 7% recovery of baseline; P < .01). These results suggest that insufficient energy production is primarily responsible for myocardial ischemic damage, whereas mechanical effects of ischemic contracture appear to play only a minor role.

This article has been cited by other articles:

				Y. Chung Oxygen reperfusion is limited in the postischemic hypertrophic myocardium Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2075 - H2084. [Abstract] [Full Text] [PDF]

				M. Kido, H. Otani, S. Kyoi, T. Sumida, H. Fujiwara, T. Okada, and H. Imamura Ischemic preconditioning-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contraction-induced myocardial injury Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H81 - H90. [Abstract] [Full Text] [PDF]

				Y. Cheng, K. A. Mowrey, V. Nikolski, P. J. Tchou, and I. R. Efimov Mechanisms of shock-induced arrhythmogenesis during acute global ischemia Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2141 - H2151. [Abstract] [Full Text] [PDF]

				R. Ramasamy, Y. Hwang, S. Bakr, and S. R. Bergmann Protection of ischemic hearts perfused with an anion exchange inhibitor, DIDS, is associated with beneficial changes in substrate metabolism Cardiovasc Res, August 1, 2001; 51(2): 275 - 282. [Abstract] [Full Text] [PDF]

				T. Ay, X. Havaux, G. Van Camp, B. Campanelli, G. Gisellu, A. Pasquet, J.-F. Denef, J. A. Melin, and J.-L. J. Vanoverschelde Destruction of Contrast Microbubbles by Ultrasound: Effects on Myocardial Function, Coronary Perfusion Pressure, and Microvascular Integrity Circulation, July 24, 2001; 104(4): 461 - 466. [Abstract] [Full Text] [PDF]

				R. Ramasamy, Y. C. Hwang, J. Whang, and S. R. Bergmann Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4 Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H290 - H297. [Abstract] [Full Text] [PDF]

				S. Vogt, D. Troitzsch, H. Abdul-Khaliq, W. Bottcher, P. E. Lange, and R. Moosdorf Improved myocardial preservation with short hyperthermia prior to cold cardioplegic ischemia in immature rabbit hearts Eur. J. Cardiothorac. Surg., August 1, 2000; 18(2): 233 - 240. [Abstract] [Full Text] [PDF]

				C. Depre, J.-L. J. Vanoverschelde, and H. Taegtmeyer Glucose for the Heart Circulation, February 2, 1999; 99(4): 578 - 588. [Full Text] [PDF]

				M. T. Stapleton, C. M. Fuchsbauer, and A. P. Allshire BDM drives protein dephosphorylation and inhibits adenine nucleotide exchange in cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1260 - H1266. [Abstract] [Full Text] [PDF]

				R. Ramasamy, N. Trueblood, and S. Schaefer Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H195 - H203. [Abstract] [Full Text] [PDF]

				C. Depre, L. Fierain, and L. Hue Activation of nitric oxide synthase by ischaemia in the perfused heart Cardiovasc Res, January 1, 1997; 33(1): 82 - 87. [Abstract] [Full Text] [PDF]

				C. Depre, J.-L. Vanoverschelde, J.-F. Goudemant, I. Mottet, and L. Hue Protection Against Ischemic Injury by Nonvasoactive Concentrations of Nitric Oxide Synthase Inhibitors in the Perfused Rabbit Heart Circulation, October 1, 1995; 92(7): 1911 - 1918. [Abstract] [Full Text]

				Y. Cheng, K. A. Mowrey, V. Nikolski, P. J. Tchou, and I. R. Efimov Mechanisms of shock-induced arrhythmogenesis during acute global ischemia Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2141 - H2151. [Abstract] [Full Text] [PDF]