Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601543
Title: The measurement, biological variation and response to acute inflammation of asymmetric dimethylarginine (ADMA)
Author: Blackwell, Scott
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2013
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Abstract:
Introduction and methods Asymmetric dimethylarginine (ADMA) is a potent endogenous competitive inhibitor of nitric oxide synthases, which has attracted considerable attention as a marker and mediator of atherosclerotic disease and as a potential mediator of multiple organ failure in critical illness due to endothelial dysfunction. However, data regarding basic aspects of its biology such as biological variation and its response to acute inflammation are lacking. Moreover, significant methodological variability has been a barrier to collating the burgeoning data available. Therefore, this thesis describes the development and validation of a reliable assay for measurement of ADMA and related compounds in plasma, urine and other biological fluids based on isocratic reverse phase high performance liquid chromatography (HPLC). This method was used to determine the biological variation of ADMA in human plasma, and its response to acute inflammation using a model of elective knee arthroplasty. Further HPLC methods for measurement of dimethylamine (DMA), the main metabolite of ADMA, and nitrate were developed and used to determine excretion of these compounds in acute inflammation to complement the observed changes in plasma ADMA concentration. Results Complete chromatographic separation of arginine, homoarginine, monomethyl-arginine, ADMA and its structural isomer SDMA was achieved, permitting their accurate quantification using a novel, non-endogenous, internal standard. The intra-individual biological variation of ADMA was found to be low at 7.4%, imposing a tight imprecision goal for analytical methods. Plasma ADMA concentration decreases rapidly during the acute inflammatory response, with a median decrease of around 30%, and a significant change already evident as little as 12 hours following the onset of inflammation. No similar change was seen in the concentration of the closely related compound SDMA. No significant increase in the urine excretion of DMA was noted during the early phase of the response, with a significant increase seen 5 days following the insult by which point the plasma ADMA concentration had returned to baseline levels. A small, but significant, decrease in nitrate excretion during the inflammatory response was seen, mirroring the observed changes in plasma ADMA. Conclusion The low biological variation of ADMA suggests physiological regulation. The rapid and significant decrease in plasma concentration during inflammation does not appear due to increased catabolism, but rather is more likely to represent increased cellular partitioning. This may be associated with an impairment in NOS activity. It is unclear whether this is of pathological significance, or represents a physiological response to regulate NO production in inflammation. Further study is warranted in relevant models, particularly with attention to intracellular concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.601543  DOI: Not available
Keywords: QD Chemistry ; QP Physiology ; RC Internal medicine
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