臺灣博碩士論文加值系統

甲基安非他命 (Methamphetamine, MA) 是一種強效且易成癮的中樞神經興奮劑，不只會影響中樞神經行為，也會引起心血管功能之異常，包括心搏過速、心肌缺血以及高血壓。MA引發的升高血壓與心跳反應主要來自其對交感神經之作用。前腹外側延腦 (rostral ventrolateral medulla, RVLM) 為中樞興奮交感神經之核區，而後腹外側延腦 (caudal ventrolateral medulla, CVLM) 則為中樞抑制交感神經之核區；已知它們在持續性與反射性交感神經血壓調節作用中扮演重要角色。此觀點暗示了RVLM與CVLM也許與MA引發的高血壓有關。麩胺酸 (glutamate) 是這些中樞交感神經相關之神經核主要調控心血管功能的神經傳導物質；許多研究指出，磷酸化RVLM上離子型通道型麩胺酸受體－NMDA受體 (N-methy-D-asparate receptors, NMDARs) ，可增強該受體功能，增加中樞交感活性之輸出，造成急性高血壓。我們的研究結果顯示，麻醉動物經由側腦室 (50、150及500 nmol) 或清醒動物經由腹腔 (2及10 mg/kg) 投與MA，皆會引發劑量相關之升高血壓；同時顯著的增加RVLM區Fos蛋白的表達量。這些已獲致的數據顯示，RVLM可能參與了MA引發急性高血壓之中樞路徑。此外，腹腔注射MA (2 and 10 mg/kg) 會使RVLM區NMDA受體次單位NR1上的磷酸化serine 896蛋白質表現量增加，而此磷酸化作用是經由C型蛋白激�� (protein kinase C, PKC)所媒介。於RVLM微量注射投與PKC抑制劑bisindolymaleimide (BIM, 4 nmol) ，則可阻斷MA於麻醉大鼠引發的升壓作用。本實驗結果推測，MA引發的心血管毒性，特別是急性高血壓，是經由PKC磷酸化RVLM上NMDA受體次單位NR1，引起中樞交感活性輸出增加，導致急性高血壓。

Methamphetamine (MA) is a strongly addictive psychostimulant that not only affects the central neurobehaviour but also cause cardiovascular dysfunctions, including tachycardia, myocardial ischemia and hypertension. MA produces increase in blood pressure and the response of heart rate mainly via sympathetic nervous system. The rostral ventrolateral medulla (RVLM), a central sympathoactivating nucleus, and caudal ventrolateral medulla (CVLM), a central sympathoinhibitory nucleus, have been well known to be critical to the tonic and reflexive sympathetic regulation of arterial blood pressure. It suggests that the RVLM and CVLM may be relevant to the hypertension induced by MA. Glutamate is the primary neurotransmitter involved in the cardiovascular regulation in the central sympathetic-related nuclei. Results from many studies have revealed that phosphorylation of the ionotropic glutamate receptor- NMDA receptors (NMDARs) on the RVLM will increase the receptor function which leads to an increase in central sympathetic outflow resulting in acute hypertension. Our data showed that intracerebroventricular (i.c.v., 50, 150 and 500 nmol) or intraperitoneal (i.p., 2 and 10 mg/kg) administration of MA increased blood pressure in a dose-dependent manner in anesthetized and conscious rats, respectively. In the meanwhile, a significant increase in the level of Fos protein was found in the RVLM after administration of MA. The available data suggested that the RVLM might involve in the central command pathway of MA-induced acute hypertension. In addition, MA (2 and 10 mg/kg; i.p.) induced a significant increase in the expression of the phosphoserine 896 protein (regulated by PKC) on NR1 subunit in the RVLM. Microinjection of the selective protein kinase C (PKC) inhibitor bisindolymaleimide (BIM, 4 nmol) into the RVLM blocked MA-induced pressor effects in anesthetized rats. Our results suggest that MA induced cardiovascular toxicity, especially acute hypertension, is associated with the phosphorylation of NMDA receptor subunit NR1 by PKC in the RVLM, which leads to an increase in central sympathetic outflow causing acute hypertension.

中文摘要 …………………………………………………………… 1
英文摘要 …………………………………………………………… 2
壹、背景介紹
一、前言 …………………………………………………………… 3
二、文獻探討 ……………………………………………………… 3
1. MA與心血管作用 ………………………………………… 3
2. RVLM及CVLM與血壓的調控 ………………………………… 5
3. NMDA受體及蛋白質磷酸化作用 …………………………… 6
貳、研究目的與實驗設計
一、理論基礎 ……………………………………………………… 9
二、研究目的 ……………………………………………… 9
三、實驗假設 ……………………………………………… 9
四、實驗設計 ……………………………………………… 10
參、實驗方法材料與詳細步驟
一、實驗動物 …………………………………………… 15
二、實驗藥物 …………………………………………… 15
三、體內試驗 (In vivo studies)
(一) 麻醉鼠模式監測血壓、心跳變化 …………… 15
(二) 清醒鼠模式監測血壓、心跳變化 …………… 17
四、體外試驗 (In vitro studies) …………………… 18
五、統計分析方法 ………………………………………… 20
肆、結果 …………………………………………………………… 21
伍、討論 …………………………………………………………… 28
陸、結論 …………………………………………………………… 32
柒、參考文獻 ……………………………………………………… 33
捌、結果附圖 ……………………………………………………… 40
附錄一 …………………………………………………………… 56

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