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Nmr Studies of Myocardial Energy Metabolism and Ionic Homeostasis During Ischemia and Reperfusion

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Nmr Studies of Myocardial Energy Metabolism and Ionic Homeostasis During Ischemia and Reperfusion J.H. Kirkels NMR STUDIES OF MYOCARDIAL ENERGY METABOLISM AND IONIC HOMEOSTASIS DURING ISCHEMIA AND REPERFUSION A BASIS FOR PROTECTIVE MECHANISMS NMR STUDIES OF MYOCARDIAL ENERGY METABOLISM AND IONIC HOMEOSTASIS DURING ISCHEMIA AND REPERFUSION A BASIS FOR PROTECTIVE MECHANISMS NMR studies naar de energie- en ionenhuishouding van het hart tijdens ischemie en reperfusie Grondslagen voor protectie (met een samenvatting in het Nederlands) Proefschrift ter verkrijgmg van de graad van doctor aan de Rijksuniversiteit te Utrecht op gezag van de Rector Magnificus, Prof. dr. J A. van Ginkel ingevolge het besluit van het College van Dekanen in het openbaar te verdedigen op dinsdag 24 oktober 1989 des namiddags te 230 uur door JOHANNES HUBERTUS KIRKELS geboren op 11 juli 1958, te Hoensbroek promotores: Prof. dr. TJ.C. Ruigrok Prof. dr. F.L. Meijler co-promotor: Dr. CJ-A. van Echteld beoordelingscommissiei Prof. dr. B. de Kruijff (Rijksuniversiteit Utrecht) Professor PA. Poole- Wilson, MD, FRCP (University of London) Prof. dr. E.O. Robles de Medina (Rijksuniversiteit Utrecht) Prof. dr. T. van der Werf (Katholieke Universiteit Nijmegen) Prof. dr. N. Westerhof (Vrije Universiteit Amsterdam) This thesis was prepared in the Laboratory of Experimental Cardiology, Heart Lung Institute, University Hospital Utrecht and formed part of Project 10 of the Inter- university Cardiology Institute of The Netherlands. The study was supported by the Wijnand M. Pon Stichting, Leusden, The Netherlands. Financial support by the Heart Lung Institute of the University Hospital Utrecht, the Interuniversity Cardiology Institute of The Netherlands and The Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged. aan mijn ouders voorRian Experiments should be planned to answer important questions, but unexpected results may lead to discovery Serendipity in cardiac metabolism H.E. Morgan CONTENTS page Chapter 1. General introduction 9 Aim of the study 30 Chapter 2. Protective effect of pretreatment with the 31 calcium antagonist anipamil on the ischemic- reperfused rat myocardium: a phosphorus-31 nuclear magnetic resonance study. Chapter 3. Possible mechanisms of the protective effect 45 of pretreatment with the calcium antagonist anipamil in ischemic-reperfused isolated rat hearts. Chapter 4. Low Ca + reperfusion and enhanced susceptibility of 61 the postischemic heart to the calcium paradox. Chapter 5. Intracellular sodium during ischemia and calcium-free 75 perfusion: a ^fa NMR study. Chapter 6. Intracellular magnesium during myocardial ischemia and 91 reperfusion: possible consequences for postischemic recovery. Chapter 7. In vivo 31P NMR study of acute regional myocardial 105 ischemia and reperfusion in the rabbit presentation of an animal model and preliminary results. Chapter 8. Human donor heart preservation studied with 125 P nuclear magnetic resonance spectroscopy. Chapter 9. General discussion 139 Chapter 10. Summary 147 Samenvatting 151 This thesis is partially based upon the work described in the following papers: TJ.C. Ruigrok, J.H. Kirkels, C J.A. van Echteld, C. Borst, F.L. Meijler. 31P NMR study of intracellular pH during the calcium paradox. J Mol Cell Cardiol 1987;19:135-139. TJ.C. Ruigrok, J.H. Kirkels. Metabolic aspects of myocardial reperfusion. In: Spaan J Ail., Bruschke A.V.G., Gittenberger-de Groot A.C. (Eds), Coronary Circulation. From Basic Mechanisms to Clinical Implications. Dordrecht, Martinus Nijhoff Publ. 1987:185-193. T.J.C. Ruigrok, JJL Kirkels, CJ.A. van Echteld, C. Borst, FJL. Meijler. Phosphorus nuclear magnetic resonance measurements of intracellular pH in isolated rabbit heart during the calcium paradox. In: Dhalla N.S., Innes I.R., Beamish R.E. (Eds), Myocardial Ischemia. Boston, Martinus Nijhoff Publ. 1987:257-263. JJH. Kirkels, TJ.C. Ruigrok, CJA. van Echteld, F.L.Meijler. Protective effect of pre- treatment with the calcium antagonist anipamil on the ischemic- reperfused rat myocardium: a phosphorus-31 nuclear magnetic resonance study. J Am Coll Cardiol 1988;ll:1087-1093. TJ.C. Ruigrok, J.H. Kirkels, CJA. van Echteld. Energy depletion due to the calcium paradox. In: de Jong J.W. (Ed), Myocardial Energy Metabolism. Dordrecht, Martinus Nijhoff Publ. 1988:215-222. JH. Kirkels, T.J.C. Ruigrok, CJA. van Echteld, F.L. Meijler. Low Ca2+ reperfusion and enhanced susceptibility of the postischemic heart to the calcium paradox. Circ Res 1989,64:1158-1164. J Ji. Kirkels, TJ.C. Ruigrok, CJA. van Echteld, C. Ceconi, R. Ferrari. Possible mech- anisms of the protective effect of pretreatment with the calcium antagonist anipamil in ischemic-reperfused isolated rat hearts. Submitted to Cardiovasc Drugs Ther. J.H. Kirkels, CJA. van Echteld, TJ.C. Ruigrok. IntraceUular magnesium during myocar- dial ischemia and reperfusion: possible consequences for postischemic recovery. J Mol Cell Cardiol, in press. CJA. van Echteld, JM. Kirkels, M. Eijgelshoven, P. van der Meer, TJ.C. Ruigrok. Intracellular sodium during ischemia and calcium-free perfusion: a ^a NMR study. Submitted to S Mol Cell Cardiol. General introduction GENERAL INTRODUCTION •m «yocardial ischemia leads to a cascade of interrelated events, which can be *•* ^-explained by a reduced availability of oxygen and substrate, and accumula- tion of metabolic waste products . In order to briefly review the consequences of ischemia it may be helpful to artificially distinguish between primary disturbances, including metabolic changes , altered ionic homeostasis , and reduced defence mechanisms against (oxygen) free radicals , and secondary consequences, mainly membrane damage and cell necrosis . Timely restoration of flow to the ischemic tissue (reperfusion) may completely reverse the detrimental effects of ischemia, but when reperfusion occurs too late, the ischemic cells will be beyond help . However, at intermediate ischemic periods 7 R reperfusion may either initiate slow metabolic and functional recovery ' , or, paradoxically, accelerate the manifestations of ischemic cell damage or give rise to specific reperfusion damage . Unfortunately, the transition from reversible to irreversible cell damage is difficult to assess. It may depend on the species studied, the degree of residual blood supply through a collateral circulation and metabolic demands during ischemia. Furthermore, if the specific conditions of reperfusion can also contribute to tissue salvage, the concept of expressing the extent of ischemic damage in terms of (ir)reversibility may even be inadequate. With the advent of PTCA and thrombolysis (early) reperfusion is becoming a clinically feasible intervention " . Additional basic knowledge is needed to further improve biochemical and functional recovery of previously ischemic myocardial tissue. In this chapter a concise introduction will be given on the consequences of myocardial ischemia and reperfusion, with an overview of the literature. Finally, the specific aim of this study will be presented. 10 General introduction A. 1 Energy metabolism during ischemia and reperfusion The heart is dependent on aerobic metabolism for energy (ATP) production, necessary for contraction, maintenance of ionic gradients and (macro)molecular synthesis . When the supply of oxygen becomes insufficient for oxidative phos- phorylation in mitochondria, the heart is said to be ischemic . The laboratory situation, in which delivery of substrate is continued in the absence of oxygen, is referred to as hypoxia. Although there are some common features in ischemia and hypoxia, there are also many differences, like the accumulation or removal of metabolic waste products ' . If oxygen is no longer available, anaerobic glycolysis will continue to produce energy ' , but at a much lower efficiency (2 mol of ATP per mol glucose as opposed to an additional 36 ATP during oxidative phosphorylation 4). The maxi- mum rate of glycolytic ATP production is less than 10 % necessary to maintain cardiac function . Due to the imbalance between energy production and energy utilization, reserve stores of ATP will be depleted during ischemia, with a concomi- 91 9S tant rise in inorganic phosphate " .However, during the initial phase of ischemia, ATP levels are temporarily maintained by delivery of high-energy phosphate bonds from creatine phosphate (CP) through the reaction catalyzed by creatine kinase: 26-28 CP2" + MgADP' + H+ <s> CT + MgATP2" Contractile work is reduced shortly after aerobic metabolism ceases ^ , prob- 31 34 ably due to acidosis or accumulation of inorganic phosphate ' j and as a result energy expenditure is reduced. Nevertheless, there is a persistent deficit between ADP phosphorylation and ATP hydrolysis that causes ATP content to decrease as the duration of ischemia is prolonged 2>16^3.25-35. When ATP levels reach a critically low level, rigor complexes will be formed by the contractile apparatus, leading to contracture ^ . ATP hydrolysis leads to a transient elevation in ADP content, a more prolonged increase in AMP, followed by the production of adenosine, inosine and hypoxan- thine, which may leave the cell ^ .Adenosine is a potent vasodilator , which may cause coronary artery dilation when it has been released in sufficient amounts to the extracellular space in the vicinity of coronary arterioles. ATP hydrolysis also 21 45 46 causes acidification of the cytosol - - > as does, to a lesser extent, the production of lactate by anaerobic glycolysis 17'26-47. The source of anaerobic glycolysis, gly- cogen, will be gradually depleted during ischemia ' , until one of
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