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dc.contributor.authorMarshall, Craigen
dc.date.accessioned2018-03-29T12:18:34Z
dc.date.available2018-03-29T12:18:34Z
dc.date.issued2007en
dc.identifier.urihttp://hdl.handle.net/1842/29249
dc.description.abstracten
dc.description.abstractThe association between elevated uric acid (UA) concentrations and cardiovascular disease is well established in epidemiology, but the possibility that UA plays a specific role in the pathophysiology of cardiovascular disease remains a matter of debate. Although there are putative mechanisms by which UA could injure the cardiovascular system, it also has a number of properties that might be considered as protective. Most notably, its role as a radical-scavenging antioxidant might be expected to mitigate the effects of increased oxidative stress, which is characteristic of most risk factors for cardiovascular disease and is an important precipitant of endothelial dysfunction. The aim of the studies described in this thesis was to examine the effects of UA on endothelial function and investigate whether UA has the potential to reverse endothelial dysfunction induced by low-density lipoprotein (LDL).en
dc.description.abstractMesenteric arteries were isolated from Wistar-Kyoto rats and the responses to a vasoconstrictor (PE, phenylephrine) and endothelium-dependent (ACh, acetylcholine) and -independent (SNP, sodium nitroprusside) vasodilators examined using perfusion myography. This model was considered advantageous because it enabled the measurement of pharmacological responses in the presence of different luminal solutions in an experimental environment that most closely mimics the conditions found in vivo. Luminal perfusion with L-NAME and/or indomethacin demonstrated that nitric oxide synthase (NOS) -derived nitric oxide (NO) was the major vasodilator released by the endothelium in response to ACh in this experimental model.en
dc.description.abstractExposure of the vascular lumen to increasing concentrations of UA (200, 400, 600pM) or vehicle solution had no effect upon the responses to PE, ACh or SNP. This implied that, in this model, acute exposure to elevated UA does not impair endothelial function. In contrast, when the lumen was perfused with increasing concentrations of LDL (250, 500 and lOOOμg/ml), maximal vasodilatation towards resting diameter in response to ACh was reduced to 42.6, 33.6 and 21.7% respectively. The failure of the NOS inhibitor LNAME to further impair vasodilatation implied that major effect of LDL was to abolish endothelium-dependent NO-mediated vasodilatation. Supplementing the perfusing LDL solution with ImM L-arginine restored endothelium-dependent responses, implying that the LDL-induced endothelial dysfunction was in part explained by a disruption of Larginine metabolism. Supplementation with the extracellular O₂ scavenger, superoxide dismutase (SOD), did not prevent the deleterious action of LDL.en
dc.description.abstractSupplementation of 250μg/ml LDL with increasing concentrations of UA (200, 400, 600μM) partially reversed the inhibition of maximal vasodilatation towards resting diameter in response to ACh to 62.2, 69.5 and 74.4% respectively. No such improvement could be achieved in the presence of L-NAME. The beneficial effect of 400μM UA upon LDL-induced endothelial dysfunction contrasted with the lack of effect of two other water-soluble antioxidants, ascorbic acid (AA) and glutathione (GSH), at the same concentration.en
dc.description.abstractThe experiments then focused on investigating the potential mechanism by which UA prevented LDL-induced endothelial dysfunction. Isolated rings of thoracic aorta from Wistar-Kyoto rats were mounted in a wire myograph and exposed to ACh in the presence of varying concentrations of UA and 250pg/ml LDL. The superfusate was then transferred to endothelium-denuded rings and caused significant vasodilation in previously unresponsive ring segments. The extent of the vasodilatation in response to the transferred solution was dependent on the concentration of UA and ox-Hb sensitive. The decay in vasodilator response if the exposure of the denuded ring was delayed had a half-life of 29 minutes. These results implied that the stimulation of an endotheliumintact vessel by ACh in the presence of both UA and LDL results in the formation of an endothelium-independent vasodilator that releases NO and may be a derivative of UA.en
dc.description.abstractIn summary, the results of these experiments suggest that acute exposure to UA in physiological concentrations does not impair either endothelium-dependent or - independent vascular responses. Conversely, UA reverses the impairment of AChinduced vasodilatation caused by LDL and does so more effectively than other high concentration hydrophilic antioxidants. Furthermore, UA appears to enable the formation of an NO-releasing compound when it is present with LDL and endothelial cells VI stimulated by ACh. The presence and nature of a possible NO-donor compound formed in these circumstances requires further investigation. Taken together, this work implies that UA exposure is not directly injurious to vascular function and may protect against the effects of LDL on the vascular endothelium. This might offer a physiological role for a compound which is found in much higher concentration in the extracellular fluids of humans than almost any other species.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2018 Block 17en
dc.titleEffects of uric acid on endothelial function and dysfunctionen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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