高血糖影響血管張力異常之性別差異：雌二醇所扮演之角色

Gender effect of hyperglycemia- induced dysfunction in vascular tone: role of 17-β estradiol

李佳彰(Chia-chang Lee)

指導教授 ： 顏嘉宏

國立屏東科技大學/農學院/生物科技研究所/碩士(2012年)

https://doi.org/10.6346/NPUST.2012.00271

摘要

已知高血糖會造成血管功能異常，即血管放鬆反應減弱和血管收縮反應增強，進而導致相關的併發症產生，例如：動脈粥狀硬化和高血壓。此外文獻指出在糖尿病的女性罹患心血管疾病的死亡率卻高於糖尿病男性。因此，(1)我們探討相同程度的高血糖引起的血管功能異常是否具有性別差異，並探討高血糖引起血管功能障礙是否有血管床的專一性。(2)在雌性大鼠高血糖引起的血管張力異常是否與雌性賀爾蒙有關。(3)雌性賀爾蒙中的雌二醇(17-β estradiol ；E2)在高血糖引起雌性的血管張力異常是否扮演著重要角色。實驗將Wistar大鼠分成七組：雄性大鼠(M)、雄性高血糖大鼠(M-DM)、雌性大鼠(F)、雌性高血糖大鼠(F-DM)、雌性卵巢摘除大鼠(OVX)、雌性卵巢摘除高血糖大鼠(OVX DM)、雌性卵巢摘除給予E2高血糖大鼠(OVX-DM+E2)，當誘導成高血糖後每兩週量測禁食八小時血糖，最後將大鼠犧牲採血取出主動脈血管與上腸繫膜動脈，進行血管的張力測量，分別以氯化鉀(Potassium chloride; KCl)和酚基麻黃素(phenylephrine; PE)來測量血管的收縮反應，乙醯膽鹼(acetylcholine; ACh)來測量血管內皮依賴性的放鬆反應，再以一氧化氮合成酶的抑制劑NG-Nitro-L-arginine Methyl Ester (L-NAME)來評估基礎一氧化氮(nitric oxide; NO)的釋放量。另外，部分主動脈血管段利用化學冷光反應，以lucigenin和NADPH偵測超氧陰離子的釋放及NADPH oxidase的活性。我們發現：(1)高血糖引起雄性大鼠主動脈血管張力異常，如PE引起的收縮反應增強，但在雌性大鼠高血糖造成主動脈的功能性障礙更加嚴重，如PE引起的收縮反應增強，ACh誘導的放鬆反應減弱、基礎NO的釋放量減少與NADPH oxidase活性增加。然而在大鼠的上腸繫膜動脈中，高血糖引起的血管功能性障礙在雄性與雌性皆沒有明顯的影響。(2)另外，將卵巢摘除後的結果高血糖在雌性大鼠所引起的主動脈功能性障礙大部分消失，除了基礎NO的釋放量，顯示女性賀爾蒙可能與高血糖在雌性大鼠所引起的主動脈功能障礙相關。(3)在卵巢摘除大鼠給予E2的結果顯示在雌性大鼠高血糖引起的主動脈功能性障礙E2應該沒有扮演著重要角色。結論高血糖在雌性大鼠中會引起比較嚴重的主動脈血管功能性障礙與卵巢分泌的雌性賀爾蒙相關，但E2似乎不是高血糖造成雌性大鼠主動脈血管產生更加嚴重的功能障礙的主要賀爾蒙。

關鍵字

高血糖 ； 血管張力 ； 雌二醇 ； 卵巢摘除

並列摘要

Several studies have demonstrated that hyperglycemia affects vascular tone regulation such as decreased vasodilatation and enhanced vasoconstriction. Vascular dysfunction has been taken as a hallmark to atherosclerosis or hypertension. Additionally the diabetic women show higher mortality of coronary heart disease than men do. Therefore, we used nicotinamide and streptozotocin to induce similar extent of hyperglycemia in male, female, ovariectomized (OVX), and OVX Wistar rats treated with estradiol (25g/kg twice a weeks) subcutaneously to investigate that whether there is a gender difference in hyperglycemia induced vascular dysfunction, and whether female sex hormones such as estradiol play a role. During the experimental period, we measure body weight weekly and fasting blood glucose every 2 weeks. In the end of study, rats were sacrificed to isolate thoracic aorta and superior mesenteric artery to evaluate vasoconstrictor response mediated by phenylephrine (PE) and potassium chloride (KCl), vasodilator response induced by acetylcholine (ACh), basal NO release assessed by L-NAME-mediated response, basal reactive oxygen species production and NADPH related oxidase activity via lucigenin-enhanced chemiluminescence. We found that: (i) hyperglycemia increased vascular response to PE, an alpha 1 receptor agonist, in male rats aorta; however, in female rats, hyperglycemia induced more severe vascular dysfunctions including increased PE- induced vasoconstriction, decreased acetylcholine- mediated endothelium-dependent vasorelaxation, decreased basal endothelial NO release, and increased NADPH related oxidase activity. However, in superior mesenteric artery, hyperglycemia had little effects on vascular functions in males and females; (ii) hyperglycemia-related vascular dysfunctions observed in female rats were not noticed in OVX rats excluding decreased basal endothelial NO release; (iii) vascular functions were not abolished in OVX+E2 rats with diabetes comparing to diabetic OVX rats. In conclusion, to aorta, female is more susceptible to hyperglycemia-mediated vascular dysfunctions than male, and female sex hormones, but not estradiol, may play an important role in the gender difference of hyperglycemia- induced aortic vascular dysfunctions.

並列關鍵字

hyperglycemia ； vascular tone ； 17β-estradiol ； ovariectomized

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