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Title: Resistance artery function in diabetes and hyperglycaemia
Author: McIntyre, Carol Ann
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Diabetes mellitus is associated with an increased risk of microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy and atherosclerosis, which account for the increased morbidity and mortality associated with this disease. There is considerable evidence that these complications are the result of vascular dysfunction, which is closely related to poor glycaemic control. This thesis studied the hypothesis that the vascular abnormalities in diabetes are the consequence of exposure to elevated blood glucose concentrations. To date the majority of studies of vascular function in diabetes have been performed using animal models. However, results from such studies have produced conflicting results and are difficult to relate to the human condition. Therefore, it would be advantageous if vascular function could be studied in vessels isolated from a human source. Due to the irregular and unpredictable nature of obtaining human vessels it was first necessary to develop protocols using animal vessels. Vessel structure was studied using a combination of histological and immunological techniques and this was complemented by functional studies using small vessel myography. Preliminary data demonstrated that storing vessels in a physiological salt solution at 4°C did not alter endothelial or vascular smooth muscle cell function and therefore human vessels could be stored for subsequent functional analysis in the knowledge that this does not adversely affect vascular function. Exposure of rat mesenteric resistance arteries to elevated glucose had no adverse effect on endothelium-dependent relaxation. However, a selective attenuation of endothelin-1 (ET-l)-induced contraction was demonstrated, perhaps indicating alterations in ET-1 receptors. Relatively few studies have investigated vascular function in human subcutaneous resistance arteries, hence it was necessary to develop techniques to characterise these vessels. This investigation demonstrated the existence of three distinct vessel types, large and small resistance arteries and veins, which can be distinguished on the basis of physical appearance, differences in response to transmural stretch and functional reactivity. Furthermore, endothelium-dependent relaxation in human subcutaneous resistance arteries was shown to be predominately mediated by an endotheliumderived hyperpolarising factor (EDHF), with little or no contribution from nitric oxide (NO) or prostacyclin (PGI2). Functional investigations in resistance arteries isolated from Type 1 and Type 2 diabetic patients demonstrated unaltered endothelium-dependent and endothelium-independent relaxation. However, there was a selective alteration in contractile function which was related to the type of diabetes. In conclusion, this study has shown that although diabetes is associated with changes in contractile function there was no evidence of impaired endothelial-dependent relaxation. The changes seen in vessels from diabetic patients did not mimic those produced by acute exposure to elevated concentrations of glucose. This suggests that if the vascular alterations observed in diabetes are due to exposure to high glucose concentrations in vivo, prolonged exposure (or factors not present in vitro) are required for abnormalities to develop.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available