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Cardiovascular function in rat models of diabetes – the roles of hyperglycemia, inflammation and oxidative stress

University of British Columbia

Diabetes increases the risk of cardiovascular disease and mortality in humans. Although many diabetes-related studies have been conducted in recent years, the underlying pathogenesis still remains unclear. The aim of this thesis was to investigate if vascular and cardiac contractile dysfunction in rat models of streptozotocin-induced type 1 and fructose-streptozotocin-induced type 2 diabetes are associated with hyperglycemia, inflammation and oxidative stress, as these factors have been linked to the development of cardiovascular abnormalities in diabetes. Cardiovascular function was assessed via measurements of blood pressure, venous tone, vascular resistance, heart rate, cardiac contractility and cardiac index in vivo in diabetic as well as control rats. Moreover, these variables were evaluated following treatment with phlorizin (a glucose lowering agent), nimesulide (a selective inhibitor of cyclooxygenase-2) or N-acetylcysteine (an antioxidant). The results showed that arterial, venous and cardiac contractile responses to noradrenaline, adrenaline and/or dobutamine were depressed, to similar extents, in both models of diabetes relative to control animals, even though the rats with fructose-streptozotocin-induced diabetes had significantly higher plasma triglyceride levels than those with streptozotocin-induced diabetes. Administration of phlorizin, nimesulide and N-acetylcysteine did not affect any of the cardiovascular variables in the control rats, but significantly improved certain vascular and/or cardiac contractile responses in the diabetic rats. Specifically, α-adrenoceptor-mediated venous constriction was augmented by phlorizin in both rat models of diabetes, whereas arterial constriction remained attenuated. Acute administration of nimesulide did not alter cardiac contractile responses, but partially restored the venous and, to a less extent, arterial constriction in the diabetic rats, while chronic treatment with N-acetylcysteine ameliorated the arterial, venous as well as cardiac contractile functions. Collectively, these results suggest that the presence of hypertriglyceridemia does not significantly worsen in vivo cardiovascular function in our fructose-streptozotocin-induced rat model of type 2 diabetes, and demonstrate that hyperglycemia, inflammation and oxidative stress are, at least in part, implicated in diabetes-associated cardiovascular contractile dysfunction. Our studies have provided valuable insights into specific benefits of targeting hyperglycemia, inflammation and oxidative stress in the management of cardiovascular complications in type 1 and type 2 diabetes.

Text

2015-04-14

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/52724

Pharmacology and Therapeutics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/