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Title: Studies into endogenous fibrinolysis in the peripheral and coronary vascular beds of man
Author: Newby, David Ernest
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Methods. Peripheral circulation. Blood flow and plasma fibrinolytic parameters were determined in both forearms using venous occlusion plethysmography and blood samples withdrawn from the antecubital fossae. The brachial artery of the non-dominant was cannulated and intra-arterial drugs administered. Plasma fibrinolytic parameters were determined using enzyme linked immunosorbant and photometric methods. The mechanisms of substance P action were explored using neurokinin type 1 receptor antagonism, nitric oxide synthase inhibition and the nitric oxide donor, sodium nitroprusside. The acute fibrinolytic response was examined in habitual cigarette smokers and patients with hypercholesterolaemia: the latter were also assessed following 6 weeks of lipid lowering therapy. Coronary circulation. Following diagnostic coronary angiography, the proximal coronary artery plaque volume was determined using computerised three dimensional reconstruction of intravascular ultrasound images. Blood flow and fibrinolytic responses to selective left anterior descending coronary artery infusion were assessed using intracoronary ultrasound and Doppler, and coronary sinus and arterial blood sampling. Results. Intrabrachial substance P infusion was well tolerated and, in contrast to endothelin-1, produced reproducible increases in forearm blood flow and tissue plasminogen activator release without affecting plasminogen activator inhibitor type 1 and von Willebrand factor concentrations. The response to substance P infusion appears to be dependent on the endothelial cell neurokinin type 1 receptor, and is, in part, mediated by the nitric oxide pathway. Whilst endothelium-dependent vasomotion was impaired in both cigarette smokers and patients with hypercholesterolaemia, tissue plasminogen activator release was diminished only in cigarette smokers and was unaffected by hypercholesterolaemia or lipid lowering therapy. Endothelium-dependent coronary vasodilatation and tissue plasminogen activator release correlated inversely with the volume of coronary artery atheroma. Conclusions. A model to assess the acute endogenous fibrinolytic capacity has been developed and characterised which was well tolerated and reproducible. Cigarette smoking, but not hypercholesterolaemia, is associated with an impairment of the acute tissue plasminogen activator release which may, in part, explain the increased propensity of smokers to sustain an acute myocardial infarction as well as to respond more favourably to thrombolytic therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available