Cardiovascular Drugs and Therapy

, Volume 9, Issue 1, pp 103–115 | Cite as

Preconditioning with a single short episode of global ischemia in the isolated working rat heart: Effect on structure, mechanical function, and energy metabolism for various durations of sustained global ischemia

  • Johannes A. Moolman
  • Sonia Genade
  • Rene Winterbach
  • Ian S. Harper
  • Keith Williams
  • Amanda Lochner
Myocardial Ischemia


Purpose Preconditioning in the setting of global ischemia, using functional recovery during reperfusion as the endpoint, has recently been demonstrated in the isolated perfused rat heart. It has been suggested that its beneficial actions have a metabolic basis. The isolated rat heart has not been fully characterized with respect to the metabolic, functional, and structural changes associated with this phenomenon in the setting of global ischemia. The purpose of this study was to determine (1) the time course of protection conferred by a single episode (5 minutes) of preconditioning; (2) changes in tissue high energy phosphates, lactate, and glycogen levels at different time intervals; and (3) morphological appearance of the heart at the end of ischemia as well as after reperfusion.Methods Isolated perfused working rat hearts were used. Preconditioning consisted of a single episode of 5 minutes of global ischemia and 15 minutes of reperfusion. Preconditioned and non-preconditioned hearts were subjected to global ischemia of 20–35 minutes duration. Functional recovery, energy metabolism (high energy phosphates, lactate, and glycogen), and structural appearance were studied at different stages.Results The functional recovery of the preconditioned hearts was significantly higher than in the corresponding nonpreconditioned group during reperfusion for all durations of ischemia longer than 25 minutes. The degree of protection observed was less than reported previously. A minor degree of energy sparing was reflected by differences in the rate of depletion of glycogen and accumulation of tissue lactate during the sustained episode of ischemia. Semiquantitative light microscopy evaluation revealed that ischemia-induced structural damage was less in the preconditioned hearts, both at the end of the sustained ischemic episode as well as after reperfusion.Conclusions A single episode of global ischemia successfully preconditions the isolated working rat heart. The protection elicited was demonstrated on a functional and structural level, and was accompanied by a small energy-sparing effect.

Key words

ischemic preconditioning global ischemia energy metabolism light microscopy ultrastructure 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium.Circulation 1986;74:1124–1136.Google Scholar
  2. 2.
    Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode.Circ Res 1990;66:913–931.Google Scholar
  3. 3.
    Yellon DM, Alkhulaifi AM, Browne E, Pugsley WB. Ischaemic preconditioning limits infarct size in the rat heart.Cardiovasc Res 1992;26:983–987.Google Scholar
  4. 4.
    Cave AC, Hearse DJ. Ischaemic preconditioning and contractile function: Studies with normothermic and hypothermic global ischemia.J Mol Cell Cardiol 1992;24:1113–1123.Google Scholar
  5. 5.
    Liu YL, Downey JM. Ischemic preconditioning protects against infarction in rat heart.Am J Physiol 1992;263(Heart Circ Physiol 32):H1107-H1112.Google Scholar
  6. 6.
    Volovsek A, Subramanian R, Rebousoin D. Effects of duration of ischaemia during preconditioning on mechanical function, enzyme release and energy production in the isolated working rat heart.J Mol Cell Cardiol 1992;24:1011–1019.Google Scholar
  7. 7.
    Osada M, Sato T, Komari S, Tamura K. Protective effect of preconditioning on reperfusion induced ventricular arrhythmias of isolated rat hearts.Cardiovasc Res 1991;25:441–444.Google Scholar
  8. 8.
    Shiki K, Hearse DJ. Preconditioning of ischemic myocardium: Reperfusion-induced arrhythmias.Am J Physiol 1987;253(Heart Circ Physiol 22):H1470-H1476.Google Scholar
  9. 9.
    Hagar JM, Hale SL, Kloner RA. Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat.Circ Res 1991;68:61–68.Google Scholar
  10. 10.
    Asimakis GK, Inners-McBride K, Medellin G, Conti VR. Ischemic preconditioning attenuates acidosis and postischemic dysfunction in isolated rat heart.Am J Physiol 1992;263:H887-H894.Google Scholar
  11. 11.
    Lange R, Ingwall JS, Hale SL, Alker KJ, Kloner RA. Effects of recurrent ischemia on myocardial high energy phosphate content in canine hearts.Basic Res Cardiol 1984;79:469–478.Google Scholar
  12. 12.
    Schott RJ, Rohmann S, Braun ER, Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium.Circ Res 1990;66:1133–1142.Google Scholar
  13. 13.
    Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart.Circulation 1991;84:350–356.Google Scholar
  14. 14.
    Tsuchida A, Miura T, Miki T, Shimamoto K, Iimura O. Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning.Cardiovasc Res 1992;26:456–461.Google Scholar
  15. 15.
    Steenbergen C, Perlman ME, London RE, Murphy E. Mechanism of preconditioning. Ionic alterations.Circ Res 1993;72:112–125.Google Scholar
  16. 16.
    Riva E, Hearse DJ. Age-dependent changes in myocardial susceptibility to ischemic injury.Cardioscience 1993;4:86–93.Google Scholar
  17. 17.
    Downey JM. Ischemic preconditioning: Nature's own cardioprotective intervention.Trends Cardiovasc Med 1992;2:170–176.Google Scholar
  18. 18.
    Walker DM, Yellon DM. Ischaemic preconditioning: From mechanism to exploitation.Cardiovasc Res 1992;26:734–739.Google Scholar
  19. 19.
    Wainwright CL. Myocardial preconditioning as the heart's self-protecting response against the consequences of ischaemia.Trends Pharmacol Sci 1992;13:90–92.Google Scholar
  20. 20.
    Edoute Y, Van der Merwe E, Sanan D, Kotzé JCN, Steinmann C, Lochner A. Normothermic ischemic arrest of the isolated working rat heart. Effects of time and reperfusion on myocardial ultrastructural, mitochondrial oxidative function and mechanical recovery.Circ Res 1983;53:663–678.Google Scholar
  21. 21.
    Opie LH, Mansford KRL, Owen P. Effect of increased heart work on glycolysis and adenine nucleotides in the perfused heart of normal and diabetic rats.Biochem J 1971;124:475–490.Google Scholar
  22. 22.
    Lamprecht W, Trautschold I. ATP: Determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Bergmeyer HU, ed.Methods of Enzymatic Analysis, 2nd English ed. New York: Academic Press, 1974:2105.Google Scholar
  23. 23.
    Victor T, Bester AJ, Lochner A. A sensitive and rapid method for separating adenine nucleotides and creatine phosphate by ion-pair reversed-phase high-performance liquid chromatography.J Chromatogr 1987;389:339–344.Google Scholar
  24. 24.
    Gutmann I, Wahlefeld AW. L-(+)-Lactate. Determination with lactate dehydrogenase and NDA. In: Bergemeyer HU, ed.Methods of Enzymatic Analysis, 2nd English ed. New York: Academic Press, 1974:1464–1468.Google Scholar
  25. 25.
    Bergmeyer HU, Bernt E, Schmidt F, Stork H. Glucose: Determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Bergmeyer HU, ed.Methods of Enzymatic Analysis, 2nd English ed. New York: Academic Press, 1974:1196–1201.Google Scholar
  26. 26.
    Atkinson DE. The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers.Biochemistry 1968;7:4030–4034.Google Scholar
  27. 27.
    Matsuda M, Catena TG, Vander Heide RS, Jennings RJ, Reimer KA. Cardiac protection by ischaemic preconditioning is not mediated by myocardial stunning.Cardiovasc Res 1993;27:585–592.Google Scholar
  28. 28.
    Schaper J, Schaper W. Reperfusion of ischemic myocardium: Ultrastructural and histochemical aspects.J Am Coll Cardiol 1983;1:1037–1046.Google Scholar
  29. 29.
    Zhai X, Lawson CS, Cave AC, Hearse DJ. Preconditioning and post-ischaemic contractile dysfunction: The role of impaired oxygen delivery vs. extracellular metabolic accumulation.J Mol Cell Cardiol 1993;25:847–857.Google Scholar
  30. 30.
    Wolfe CL, Sievers RE, Visseren FLJ, Donnelly TJ. Loss of myocardial protection after preconditioning correlates with the time course of glycogen recovery within the preconditioned segment.Circulation 1993;87:881–892.Google Scholar
  31. 31.
    Neely JR, Grotyohann LW. Role of glycolytic products in damage to ischemic myocardium: Dissociation of adenosine triphosphate levels and recovery of function of reperfused hearts.Circ Res 1984;55:816–824.Google Scholar
  32. 32.
    Dennis SC, Gevers W, Opie LH. Protons in ischemia: Where do they come from; where do they go to? [editorial]J Mol Cell Cardiol 1991;23:1077–1086.Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Johannes A. Moolman
    • 1
  • Sonia Genade
    • 3
  • Rene Winterbach
    • 2
  • Ian S. Harper
    • 3
  • Keith Williams
    • 3
  • Amanda Lochner
    • 3
  1. 1.Department of Internal MedicineUniversity of StellenboschTygerbergRepublic of South Africa
  2. 2.Department of Medical Physiology and Biochemistry, Faculty of MedicineUniversity of StellenboschTygerbergRepublic of South Africa
  3. 3.Programme for Experimental BiologySouth African Medical Research CouncilTygerbergRepublic of South Africa

Personalised recommendations