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Title: Metabolic aspects of the hypoxic heart
Author: Wardle, Catherine A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Coronary heart disease is a major cause of death in Western society. Many studies have demonstrated the importance of lipid metabolism in the deterioration in cardiac function and the development of lethal arrhythmias during ischaemia. It has been suggested that a TAG-NEFA (triacylglycerol - non-esterified fatty acid) 'wasteful' cycle exists in the ischaemic heart and that increased operation of the cycle depletes ATP (adenosine triphosphate) supplies for the energy dependent ion pumps, disturbs membrane potentials and therefore causes arrhythmias. The aim of this thesis was to quantify energy wastage due to the operation of the TAG-NEFA cycle in the heart during oxygen deprivation. The hypoxic, isolated, perfused rat heart was used as the experimental model. Cannulation of the pulmonary artery allowed anaerobic sampling of coronary effluent for measurement of blood gases, and therefore calculation of oxygen uptake. Glycerol release was used as an index of TAG breakdown. Lactate production and tissue concentrations of ATP, CP (creatine phosphate), glycogen, α-glycerophosphate, glycerol and TAG were measured. The rate of TAG-NEFA cycling could therefore be calculated. The influence of severity of hypoxia on the rate of TAG-NEFA cycling was studied. A positive correlation between severity of hypoxia and energy utilization by the operation of the cycle was demonstrated. However, even during severe hypoxia (10% O_2, 85% N_2, 5% CO_2), the proportion of the total ATP produced during hypoxia utilized in the operation of the cycle was small (less than 3%). The influence of age, fasting(48h) and obesity on the operation of the TAG-NEFA cycle during normoxia and hypoxia was also studied. A five-fold difference in myocardial TAG concentration was found to be of little importance in determining the rate of the TAG-NEFA cycle. The rate of cycling was reduced in fasted rats. The role of endogenous catecholamines in the metabolic changes induced by hypoxia was investigated. Myocardial noradrenaline release could not be stimulated by oxygen deprivation. In contrast to isoprenaline-stimulated glycerol release, hypoxia-stimulated glycerol release could not be inhibited by β-adrenoceptor blocking agents. Furthermore, depletion of endogenous catecholamines by pretreament of rats with 6-hydroxydopamine caused only a 30% reduction in hypoxia stimulated glycerol release. In conclusion: 1) The operation of the TAG-NEFA cycle during hypoxia does not appear to cause a major drain on high energy phosphate supplies in the heart. 2) The rate of cycling is independent of myocardial TAG concentrations. 3) Glycerokinase activity can be demonstrated in the rat heart. 4) Glycerol release during hypoxia is mediated by non-adrenergic mechanisms and cannot be assumed to be an accurate reflection of myocardial lipolysis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available