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This dissertation, Endothelial Dysfunction and Changes in Vascular Smooth Muscle Responsiveness in Femoral Arteries of Rats With Type I Diabetes by Yi, Shi, 史懿, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract Endothelial dysfunction and changes in vascular smooth muscle responsiveness in femoral arteries of rats with type I diabetes Submitted by SHI Yi For the degree of Doctor of Philosophy at the University of Hong Kong in September 2006 The present experiments were designed to study the endothelial dysfunction and changes of vascular smooth muscle responsiveness in femoral arteries from streptozotocin-induced type I diabetic rats. NO-mediated relaxations were impaired slightly in arteries from streptozotocin-treated rats. The calcium ionophore, A23187 caused endothelium- dependent relaxations in arterial rings contracted by phenylephrine, but endothelium- dependent contractions in quiescent preparations. The endothelium-dependent contraction to A23187 was augmented in femoral arteries from streptozotocin-treated rats as early as four weeks after the injection of streptozotocin. Indomethacin (inhibitor of cyclooxygenase) and S 18886 (blocker of TP-receptor) prevented the response in rings of femoral arteries with endothelium from streptozotocin-treated rats. Dazoxiben (inhibitor of thromboxane A synthase) reduced the endothelium- dependent contractions. These results suggested that the endothelium-dependent contracting factors involved thromboxane A, which activated TP-receptors. Upregulation of COX-1 was observed, confirming the role of cyclooxygenase in the - i - endothelium-dependent contraction. Twelve weeks after streptozotocin-induced diabetes, the endothelium-dependent contraction was further augmented. A combination of S 18886 with blockers of EP -receptors (AH6089 and SC19220) was required to block endothelium-dependent contractions, suggesting that at this later stage, the endothelium-dependent contraction induced by A23187 involved prostanoids acting at both TP- and EP1-receptors. It also indicated a progressive change in the nature of the endothelium-derived contracting factor in the course of diabetes. The endothelium-dependent contractions was reduced by tiron, catalase, diethyldithiocarbamic acid (DETCA), MnTMPyP and deferoxamine, suggesting that reactive oxygen species are involved in the response. The level of reactive oxygen- derived free radicals was higher in the femoral arteries with endothelium from streptozotocin-induced diabetes under basal condition and further increased with stimulation of A23187. This suggests that oxygen-derived free radicals contribute to the endothelium-dependent contraction in the streptozotocin-treated rats. The function of vascular smooth muscle was also altered with the progression of diabetes. Twelve weeks after the injection of streptozotocin, rings of femoral arteries without endothelium from streptozotocin-treated rats exhibited a reduced maximal contraction to potassium chloride, phenylephrine and U46619, but a hyperresponsiveness to U46619 and phenylephrine. Chronic treatment with apocynin (inhibitor of NADPH oxidase) restored the normal response of the vascular smooth muscle. Inhibitors of cyclooxygenases (COX-1 or COX-2) reversed the hyperresponsiveness to phenylephrine and U46619. The observed upregulation of COX-1 and COX-2 proteins in the vascular smooth muscle was reversed by chronic apocynin treatment. These observations suggest that the reactive oxygen species - ii - derived from NADPH o

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