| Summary: | The metabolic syndrome is a cluster of cardiovascular risk factors and is a global health concern. The most accepted and unifying hypothesis proposes that insulin resistance is the major common underlying abnormality that describes the metabolic syndrome and links it to the development of cardiovascular disease. The fructose-fed rat is an animal model that exhibits several features observed in the metabolic syndrome including insulin resistance, hyperinsulinemia, hypertriglyceridemia and hypertension. This animal model is used to study the relationship between these metabolic disturbances and hypertension. Numerous mechanisms have been proposed to mediate the link between insulin resistance and hypertension. The objectives of this thesis were to further investigate the underlying mechanisms that have been proposed to contribute to the development of hypertension in fructose-fed rats through the use of various pharmacological agents. We demonstrated that chronic treatment with bosentan, a dual endothelin receptor antagonist, L-158,809, an angiotensin receptor antagonist, prazosin, an α₁-adrenoceptor antagonist or etanercept, a soluble recombinant fusion protein consisting of the extracellular ligand binding domain of tumor necrosis factor receptor type 2, prevented the development of fructose-induced hypertension without affecting insulin levels or insulin sensitivity. These results suggest that increased production and/or activity of the endothelin system, renin angiotensin system or sympathetic nervous system contribute to the development of hypertension through insulin-independent mechanisms. Both the endothelin system and renin angiotensin system are crucial players in the development of fructose-induced hypertension, with endothelin-1 contributing its effects through modulation of angiotensin II. Overactivation of the sympathetic nervous system contributed to the development of hypertension, but does not appear to be an initial, precipitating mediator. Chronic etanercept treatment prevented the development of hypertension by improving vascular function and restoring endothelial nitric oxide synthase expression. Therefore, the pathogenesis of hypertension in fructose-fed rats is complex in nature and involves numerous pathways that do not necessarily function independently from one another. === Pharmaceutical Sciences, Faculty of === Graduate
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