Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733387
Title: Intracellular sodium and the matching of ATP supply to demand in the heart
Author: O'Brien, Brett Anthony
ISNI:       0000 0004 6497 9801
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
There is convincing evidence that myocardial intracellular Na+ overload ([Na]i) and metabolic derangement are two important and interconnected pathophysiological features of heart failure. Whether [Na]i elevation plays a causative role in ATP supply-demand mismatching in the heart is unknown. A number of mitochondrial enzymes are stimulated by mitochondrial calcium (Cam) during contraction thereby sustaining production of reducing equivalents to maintain ATP supply. It is postulated that this stimulation is perturbed when [Na]i is high due to increased Cam efflux and that this may be linked with derangement in ATP supply-demand matching. This thesis tests the hypothesis that [Na]i elevation alters intermediary metabolism and energetics in the isolated perfused heart from healthy rats. [Na]i elevation was induced by perfusion with the Na+/K+ ATPase (NKA) inhibitor, ouabain, and measured in real-time using triple quantum filtered (TQF) 23Na nuclear magnetic resonance (NMR) spectroscopy. Blebbistatin was used to transiently uncouple inotropy to better elucidate [Na]i-dependent from inotropy-dependent effects on metabolism and energetics. Real-time 31P NMR measurements showed a transient increase or decrease in both PCr and Pi that mirrored a transient increase or decrease in inotropy. However PCr levels returned to baseline at the end of the protocol while there was a strong negative correlation between [Na]i and [ATP] independent of inotropy. End-point metabolomics were assessed using high resolution 1H NMR and liquid chromatography tandem mass spectrometry (LC-MS/MS). Malate (and more tentatively fumarate) were elevated, suggesting a possible link between [Na]m and TCA cycle activity in the perfused heart. Increased 13C incorporation from [U]-13C-glucose inferred higher TCA cycle activity in hearts with [Na]i overload in the absence of elevated inotropy. This thesis supports that [Na]i elevation can cause ATP supply-demand mismatching in the heart and that increased TCA cycle activity is a possible (mal)adaptive response.
Supervisor: Eykyn, Thomas Roger ; Shattock, Michael Jonathan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.733387  DOI: Not available
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