在許多代謝異常的現象，包括高胰島素血症(Hyperinsulinemia)、胰島素阻抗(Insulin resistance)及肥胖等，常伴隨著高血壓一併發生。Reaven將上述這群密不可分且經常同時存在之危險因子統稱為「X症候群(Syndrome X)」。在臨床報告中發現伴隨有高胰島素血症或胰島素阻抗之高血壓病患，其血漿中內皮素-1的濃度均較正常人為高。在過去活體與離體的研究報告中指出，胰島素的確可以增加內皮素的製造及分泌。一氧化氮是一種強力的血管舒張物質，在過去的離體研究報告中指出，細胞中的一氧化氮會受胰島素的刺激而增加，又有離體血管的研究報告指出，在高血壓的情形下，血管舒張方面是受損的。因此，本實驗的目的便是在探討以外源性胰島素誘發高胰島素血症合併高血壓之大白鼠實驗模式中，一氧化氮在血管舒張方面所扮演的角色。在本實驗中，所使用的實驗動物為大白鼠。透過包埋在雄性Sprague-Dawley大白鼠背部皮下的滲透性小膠囊，分別對大白鼠進行人體胰島素(1 unit/rat/day)或生理食鹽水的灌注。來觀察大白鼠體內胰島素的濃度及血壓的變化。血漿中胰島素濃度是利用放射性免疫分析法測得，大白鼠的心跳、收縮壓、平均動脈壓及舒張壓則是利用尾部環帶充氣法(Tail-cuff method)進行監控。實驗進行到第二週控制組大白鼠之血壓開始上升，至五~七週始達到高穩定態，於第八週進行麻醉插管的實驗。分別由靜脈注射不同濃度的乙醯膽鹼(Acetylcholine 0.1、0.3、0.5、1、3、5mg/kg)以及一氧化氮的抑制劑L-NAME(75mg/kg)，由接在動脈上的多功能記錄儀觀察其血壓的變化。實驗結果發現，在胰島素灌注八週後，乙醯膽鹼對於血壓下降的作用，相較於對照組有變差的情形。而給予了L-NAME之後，平均動脈壓之變化值又較對照組高。在離體的脂肪細胞實驗中，發現在胰島素灌注大白鼠之脂肪細胞上，胰島素所促進之2-去氧葡萄糖被吸收的能力有下降的情形，且在胰島素受器競爭結合的實驗中，胰島素與受器的結合力明顯較對照組之脂肪細胞差。說明了在這個高血壓的動物模式中伴隨有胰島素阻抗的現象存在。由上述結果顯示，在外源性胰島素灌注的大白鼠動物模式中，造成之高血壓伴隨有高胰島素血症及胰島素阻抗之現象，而經由乙醯膽鹼降血壓的能力受損，L-NAME造成平均動脈壓的升高量較對照組大，間接證明在高血壓時血液中一氧化氮增加量較為顯著，因此在這一類高血壓中，一氧化氮可能扮演著一種保護的角色。

Endothelium constitutes the inner lining of all blood vessels, not simply as a barrier between the blood-stream and the vascular smooth muscle, but also as a modulator of the vascular function. Endothelial cells have been shown to generate nitric oxide (NO), a vasodilator, and endothelin-1 (ET-1), a potent vasoconstrictor. The balance between ET-1 and NO may play an important role in blood pressure regulation. Previous studies found that ET receptor antagonist blunts hyperinsulinemia-induced hypertension in rats. However the role of NO in this model has not been defined. The purpose of my proposed study is to evaluate the changes of NO-mediated vasodilatation in insulin-induced hypertensive rats. Male Sprague-Dawley rats initially weighing 250-300g will be used for the experiments. Human insulin (1 unit/day) or saline will be infused into rats via subcutaneously implanted osmotic minipumps for 8 weeks. The systolic blood pressure, mean blood pressure, diastolic blood pressure and heart rate will be measured twice a week by tail-cuff method. Plasma level of insulin will be measured by radioimmunoassay(RIA) and glucose by glucose analyzer. The first purpose of this study were to test exogenous insulin infusion can induce hyperinsulinemia, insulin resistance and hypertension in rats. The second purpose were to measure the insulin binding activity and to evaluate the ability of glucose uptake in adipocytes isolated from insulin-infused rats and normal rats. After rats develop hypertension, acetylcholine will be administrated to measure the NO-mediated vasodilatation in vivo. There were significant differences in insulin binding and glucose uptake experiment between two groups. After NO inhibitor (L-NAME) intravenous administration, the DMBP in insulin-infusion group were higher than control. The dose response curve of acetylcholine was significant difference in two groups. In conclusion, chronic exogenous insulin infusion induces hyperinsulinemia, insulin resistance and hypertension. The results indicate that the reducing blood pressure ability of acetylcholine was impaired in insulin infusion rats and NO may play a protective role in hyperinsulinemia-induced hypertension.

中文摘要…………………………………………………………… 1
緒論………………………………………………………………… 3
實驗目的…………………………………………………………… 6
材料與方法………………………………………………………… 7
結果………………………………………………………………… 18
討論………………………………………………………………… 24
結論………………………………………………………………… 30
參考文獻…………………………………………………………… 31
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