臺灣博碩士論文加值系統

在過去的臨床及動物模式的研究證明中顯示，胰島素阻抗及高胰島素血
症和原發性高血壓有顯著的關聯性，而且以往研究報告亦顯示了腎素-血管張力素系統，特別是其中的血管張力素II的作用，可能在此機制中扮演了升高血壓和/或導致胰島素阻抗的角色。
本實驗的目的為探討AT2接受器(AT2R)及AT1接受器(AT1R)在果糖誘發高血壓及胰島素阻抗的動物模式中其是否被活化及其間可能的交互作用。本實驗以SD大白鼠為實驗對象，各組在麻醉狀態下進行插管手術，做左側股靜脈插管以持續灌流葡萄糖、胰島素、藥物及3H3-glucose溶液，另做左側股動脈插管，以供抽取動脈血及測量動脈壓。實驗期間合併3H3-glucose灌流執行正常血糖高胰島素血症箝制試驗，此實驗分為三個階段:第一階段，開始灌流3H3-glucose直到實驗結束，第一階段目的在檢驗各組在基本狀態下葡萄糖代謝速率的變化，第二階段開始合併灌流藥物、vehicle溶液及不定量的葡萄糖水溶液(20% dextrose)，目的在於觀察在有藥物的影響之下，血壓及葡萄糖代謝速率的變化，第三階段正常血糖高胰島素血症箝制期間再合併給予胰島素(8 mU/kg/min)及不定量的葡萄糖溶液，觀察各組高胰島素誘發血壓及葡萄糖代謝變化的情形。
實驗結果顯示，餵食果糖的大白鼠組其平均動脈壓和控制組比較起來有明顯上升的情形，給予AT2R拮抗劑後血壓上升程度較果糖餵食組更為明顯，在急性或慢性給予AT1R拮抗劑治療後，其血壓則有明顯下降的現象，然而合併AT1及AT2R拮抗劑急性治療，則防止AT1R拮抗劑所導致的降血壓作用，但在慢性給予AT1R拮抗劑治療下，合併給予AT2R拮抗劑則不影響其作用。大白鼠在餵食果糖後其胰島素刺激全身性葡萄糖吸收、儲存及糖解作用，增加速率顯著低於控制組，而急性給予AT1R拮抗劑則明顯改善其葡萄糖吸收及糖解作用，然而其肝臟葡萄糖產生速率則為明顯上升，慢性給予AT1R拮抗劑則會改善胰島素對葡萄糖吸收、儲存及糖解作用，亦同時改善胰島素抑制肝臟葡萄糖產生速率，急性給予AT1R拮抗劑所產生的改善作用，同時若合併AT2R拮抗劑的給予，則防止了此現象的產生，但在慢性給予AT1R拮抗劑時，合併給予AT2R拮抗劑則不影響其作用。
綜合以上結果得知AT1R及AT2R在果糖餵食所誘發之高血壓及胰島素阻抗之動物模式中其活性皆明顯增加，且AT2R所產生保護的機制在AT1R作用被抑制的情況下，更有明顯作用。然而慢性AT1R拮抗劑治療明顯地減少AT2R在AT1R拮抗劑所造成果糖餵食鼠血壓下降及改善胰島素阻抗機制中扮演角色的重要性。

Backgrounds:
Numerous clinical and animal studies have demonstrated that essential hypertension is correlated with insulin resistance and hyperinsulinemia. It has also shown that the renin-angiotensin system (RAS), especially the angiotensin II may play important role in the development of either hypertension or insulin resistance in several insulin-resistant and hypertension animal models. However, the pathological roles of AT1R and AT2R in the link of these cardiovascular and metabolic dysfunctions are not fully determined.
Purpose:
The aim of the study was to access that activation and interaction of AT1R and AT2R in fructose-induced hypertension and insulin resistance in rats.
Materials and methods:
Male Sprague-Dawley rats were fed 60% fructose-enriched or regular chow diets for 4 weeks before acute experiment. At the end of wks 4, the rats were cannulated under anesthesia. After recovery for 3 days, all experiment was consisted of a 30-min control period and two 90-min test periods. [3H3] glucose as tracer was infused intravenously throughout the experiment. After control period, glucose was infused peripherally as needed to clamp euglycemia. During the two test periods, AT1R antagonist, (losartan, 10mg/kg i.v. bonus at time 0) and AT2R antagonist (PD123319, 50μg/kg/min, i.v.) alone or in combination were given to separate fructose-fed group. In the first test (basal) period, only saline was infused in all groups; in the second test (euglycemic hyperinsulinemic clamp, EHC) period, additional insulin was infused to evaluate insulin-dependent glucose metabolism. In chronic losartan-treated groups, losartan was given by adding in drinking water (10mg/kg/day) for 2 wks before acute experiment. Vehicle or PD123319 was given during two test periods to evaluate the attenuation of AT2R under chronic losartan treatment in fructose induced hypertension and insulin resistance in rats.
Result:
The results showed that plasma glucose levels were not significantly changed in all groups throughout the experiments. Plasma insulin levels were three fold higher in fructose-fed rats than in normal rats with regular diet in the control period and did not change by losartan and/or PD123319 treatment. During EHC period, insulin infusion significantly increased plasma insulin level by 8 folds. Acute losartan treatment reduced the elevated mean blood pressure (MAP) of fructose-fed rats to normal level. In contrast, acute PD123319 infusion further increased MAP of fructose-fed rats. However, the depressor effect of losartan and the pressor effect of PD123319 were not exhibited when both agents were given in combination. During EHC period, acute administration of losartan, but not PD123319, significantly increased the rate of whole body glucose uptake mainly by increasing the rate of whole body glycolysis. However, it further inhibited the insulin-mediated suppression of hepatic glucose production. The effects of insulin sensitivity were not observed when PD123319 was superimposed on losartan. Chronic losartan treatment significantly reversed fructose-induced hypertension and insulin resistance to normal levels. PD123319 infusion did not change the depressor and metabolic effects of losartan treatment.
Conclusion:
These data showed that (1) activation of both AT1R and AT2R are existed in fructose-induced hypertensive and insulin resistant rats. (2) Activation of AT2R counterbalances the pressor and insulin desensitizing effects of AT1R in this hypertensive model. (3) Activation of AT1R is important for the functional activation of AT2R in fructose-induced insulin resistance and hypertension in rats.

頁次
目 錄…………………………………………………………… I
表 次……………………………………………………………III
圖 次……………………………………………………………IV
中文摘要……………………………………………………………VI
英文摘要………………………………………………………….. VIII
第一章 前言……………………………………………………….1
第一節 腎素-血管張力素系統………………………………...3
第二節 AT1R和AT2R與血壓調控及其間可能的交互作用……4
第三節 RAS與胰島素阻抗……………………………………..8
第四節 動物模式………………………………………………10
第二章 實驗目的…………………………………………………11
第三章 材料與方法………………………………………………12
第一節 實驗材料………………………………………………12
第二節 儀器設備………………………………………………12
第三節 化學製劑………………………………………………13
第四節 實驗設計………………………………………………15
第五節 測定方法與計算………………………………………20
第四章 結果……………………………………………………..29
第一節 AT1R拮抗劑的存在與否對AT2R作用的影響……….29
第二節 AT2R在給予急性或慢性AT1R拮抗劑治療中所扮演
的角色………………………………………………..34
第五章 討論……………………………………………………..42
第六章 結論……………………………………………………..53
附錄………………………………………………………………..54
參考文獻…………………………………………………………..74
表 次
Table1、各組體重、血比容、血漿三酸甘油酯濃度及3H3-glucose
放射活性之變化……………………………………………….54
Table2、各組體重、血比容、血漿三酸甘油酯濃度及3H3-glucose
放射活性之變化……………………………………………….55
圖 次
第一節 AT1R拮抗劑的存在與否對AT2R作用的影響
Fig1-1. 各組灌流期間血漿葡萄糖濃度及葡萄糖灌流速率之變化..56
Fig1-2. 各組灌流期間血漿胰島素濃度及胰島素灌流速率之變化..57
Fig1-3. 各組灌流期間平均動脈壓之變化…………………………..58
Fig1-4. 各組灌流期間心跳值之變化………………………………..59
Fig1-5. 各組灌流期間肝臟葡萄糖產生速率之變化………………..60
Fig1-6. 各組灌流期間全身性葡萄糖吸收速率之變化……………..61
Fig1-7. 各組灌流期間全身性葡萄糖儲存速率之變化……………..62
Fig1-8. 各組灌流期間全身性糖解作用速率之變化………………..63
Fig1-9. 各組灌流期間血漿一氧化氮代謝物(NOx)之變化…………64
第二節 AT2R在給予急性或慢性AT1R拮抗劑治療中所扮演
的角色
Fig2-1. 各組灌流期間血漿葡萄糖濃度及葡萄糖灌流速率之變化..65
Fig2-2. 各組灌流期間血漿胰島素濃度及胰島素灌流速率之變化..66
Fig2-3. 各組灌流期間平均動脈壓之變化…………………………..67
Fig2-4. 各組灌流期間心跳值之變化………………………………..68
Fig2-5. 各組灌流期間肝臟葡萄糖產生速率之變化………………..69
Fig2-6. 各組灌流期間全身性葡萄糖吸收速率之變化……………..70
Fig2-7. 各組灌流期間全身性葡萄糖儲存速率之變化……………..71
Fig2-8. 各組灌流期間全身性糖解作用速率之變化………………..72
Fig2-9. 各組灌流期間血漿一氧化氮代謝物(NOx)之變化…………73

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