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研究生:楊紫麟
研究生(外文):Tzyy-Lin Yang
論文名稱:Valsartan降血糖作用之研究
論文名稱(外文):Antihyperglycemic Effect of Valsartan
指導教授:鄭瑞棠鄭瑞棠引用關係
指導教授(外文):Jei-Tung Cheng
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:87
中文關鍵詞:第一型糖尿病
外文關鍵詞:type I diabetesvalsartan
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Valsartan在臨床已被用來治療高血壓。在活體實驗方面,靜脈注射valsartan到streptozotocin誘發類似人類第一型糖尿病的大白鼠,可產生劑量相關性的降血糖作用。對於外給葡萄糖進行的葡萄糖挑戰試驗(glucose challenge test) ,valsartan可增加正常Wistar大白鼠對葡萄糖的利用率。文獻指出,Deoxycorticosterone acetate (DOCA) salt-hypertensive rats體內angiotensin II濃度會增高(Jackson et al., 1999),valsartan對於DOCA salt-hypertensive rats並無降血糖作用;這個現象能隨著ACE抑制劑降低了體內angiotensin II濃度而被逆轉。由此可知,valsartan降血糖作用與angiotensin II受體的阻斷有關。另一方面,在嗎啡μ型受體剔除(knockout)之第一型糖尿病小鼠,以靜脈注射的方式給予能產生降血糖作用劑量的valsartan,原本的降血糖作用卻消失了;在第一型糖尿病大白鼠方面,valsartan原本會促進體內的腦內啡(β-endorphin)上升的作用也因為兩側腎上腺摘除而消失了。由於腎上腺會分泌腦內啡,並作用於嗎啡μ型受體。因此,valsartan乃刺激腎上腺分泌腦內啡來產生降血糖的作用。同時,這個作用並不是由於valsartan的降血壓引致的反射作用來刺激腎上腺分泌腦內啡。並且,由離體腎上腺處理angiotensin II或valsartan實驗得知,angiotensin II會抑制離體腎上腺釋放腦內啡,而valsartan會抑制angiotensin II的作用使腦內啡釋放。為了瞭解valsartan降低血糖的作用機轉,就以尾靜脈注射的方式,注射有效劑量的valsartan到第一型糖尿病大白鼠身上,除了降低血糖外,亦可增強大白鼠骨骼肌之葡萄糖轉移蛋白﹙GLUT4﹚mRNA及蛋白質的表現,也會降低第一型糖尿病大白鼠肝臟之解糖酵素﹙PEPCK﹚mRNA及蛋白質的表現﹔以上的作用能被naloxone或naloxonaxzine所解消。綜合以上所得結果而知,在第一型糖尿病大白鼠中,valsartan的降血糖效果乃是藉由阻斷腎上腺的angiotensin II接受體而降低了第一型糖尿病大白鼠的高血糖現象。
Valsartan is clinically used in the management of hypertension. In the present study, a dose-dependent lowering of plasma glucose level was observed in both fasting streptozotocin (STZ)-induced diabetic rats and Wistar rats after intravenous injection of valsartan at 30 min. Valsartan at effective dose (0.2mg/kg, i.v.) significantly attenuated the increase of plasma glucose induced by intravenous glucose challenge test in Wistar rats. Injection of valsartan at the effective dose increased plasma β-endorphin concentration in STZ-diabetic rats. Plasma glucose lowering action of valsartan at the dose effective in diabetic rats disappeared in opioid μ-receptors knockout mice but was still observed in wild-type mice. On the other hand, bilateral adrenalectomy resulted in the loss of plasma glucose lowering effect of valsartan. The higher plasma angiotensin II level in DOCA salt-hypertensive rats(Jackson et al., 1999), abolished the antihyperglycemic effect of valsartan. The In vitro study showed that angiotensin II inhibitsβ-endorphin release from isolated adrenal gland. The mRNA and protein levels of glucose transporter subtype 4 (GLUT4) in soleus muscle were raised by valsartan after repeated treatment for 3 day in STZ-diabetic rats. In addiction, similar repeated treatment with valsartan reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetoc rats to the nomal level. Pharmacological inhibition of opioid μ-receptors abolished this effect of valsartan. These results suggest that angiotensin II might inhibit β-endorphin release and valsartan can enhance β-endorphin release through blocking of angiotensin II receptors.
目錄
頁數
中文摘要 3
英文摘要 4
縮寫表 5
第一章 緒論 6
第二章 實驗方法及材料 9
第三章 結果 32
第四章 討論 46
第五章 結論 54
參考文獻 55
附圖 64
自述 87
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