乙型血管張力素 (angiotensin II, Ang II) 不管在周邊或是中樞神經皆有調控生理機能的作用。在大鼠腦幹孤立束核 (nucleus tractus solitarii, NTS) 乙型血管張力素會透過其第一型接受器來調控中樞心血管的作用並導致高血壓的發生。在我們實驗室之前的研究曾指出在大鼠的孤立束核若是抑制了一氧化氮的形成，會導致高血壓的發生。在過去的文獻中也發現自發性高血壓大鼠 (spontaneously hypertensive rat, SHR)的孤立束核中乙型血管張力素的活性較高，並且會透過與乙型血管張力素第一型接受器 (angiotensin II type-1 receptors, AT1R) 的結合而產生了活化氧 (reactive oxygen species, ROS)。但乙型血管張力素如何造成高血壓的分子機制目前還尚未明瞭。所以本實驗之目的想更進一步地探討乙型血管張力素在孤立束核中心臟血管調控之分子機制。在先期實驗中，我們使用16週大的雄性自發性高血壓大鼠給予每天每公斤30毫克的乙型血管張力素第一型接受器阻斷劑 losartan，或是在飲水中加入每天每公斤1毫莫耳的超氧化物歧化酶相似物
tempol 持續兩週，且每隔3-4天均測量其尾動脈壓。結果顯示自發性高血壓大鼠
在餵養 losartan 或是 tempol 4天後，其血壓較未餵養藥物的自發性高血壓大鼠
已有明顯的降低，且血壓會緩慢並持續地降低。此外，我們也發現在給予藥物治
療的兩組動物，其孤立束核中一氧化氮的含量比未給予藥物治療的高血壓大鼠
高。然而未給予藥物治療的高血壓大鼠孤立束核中活性氧的含量卻較給予藥物治療的兩組大鼠高。這些結果顯示出當抑制了自發性高血壓大鼠孤立束核中乙型血
管張力素透過其第一型接受器的作用後，其活性氧含量會下降且血壓也有顯著的
降低。另外，在西方墨點與免疫組織染色中也觀察到當餵食藥物後孤立束核中神
經性一氧化氮合成酶 (neuronal nitric oxide synthase, nNOS) 的活性比高血壓大
鼠有顯著性的提高，但內皮性與誘發性一氧化氮合成酶則沒有此現象。所以我們
的實驗結果也顯示了神經性一氧化氮合成酶在自發性高血壓大鼠孤立束核中一
氧化氮的生成以及血壓的調控可能扮演著重要的角色。而在探討乙型血管張力素
如何影響神經性一氧化氮合成酶的活性方面，利用共同免疫沉澱、激酶分析以及
西方墨點分析，我們發現在大鼠的孤立束核中神經性一氧化氮合成酶在自發性高
血壓大鼠的孤立束核中會與RSK和ERK1/2有相互關係的存在，並且也進一步證
實了ERK1/2會透過活化RSK來促進神經性一氧化氮合成酶的磷酸化而使得一氧
化氮的產生增加。所以我們的實驗結果顯示乙型血管張力素會透過其第一型接受
器導致活化氧含量的上升而使得ERK1/2與RSK去活化後，抑制了神經性一氧化
氮合成酶造成了孤立束核中一氧化氮的減少而影響了心臟血管作用的調控。

Angiotensin II (Ang II) exerts diverse physiological actions in both peripheral and central nervous system. It has been demonstrated to implicate in central mechanisms leading to hypertension in the nucleus tractus solitarii (NTS) of rats, and mediated by the type-1 receptors (AT1R). Our previous studies already suggested that inhibition of NO synthesis in the NTS causes sustained hypertension. It was reported that the activity of Ang II was higher in the NTS of spontaneously hypertensive rat (SHR) and AT1R are colocalized in the neurons of the NTS, providing the local reactive oxygen species (ROS) production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain uncertain. In the present study, we investigated the possible signal pathways involved in the cardiovascular regulation of Ang II in the NTS. Male SHR was treated with AT1R blocker, losartan (30 mg/kg/day) or superoxide dismutase (SOD) mimetic, tempol (1 mM/kg/day) for two weeks, systolic blood pressure was decreased significantly in losartan- or tempol-treated SHR. The NTS was excised for dihydroethidium (DHE) staining, NO analysis, immunoblotting and immunohistochemistry. Our results demonstrated that DHE staining revealed of ROS was much more in the NTS of SHR than in the NTS of wistar-Kyoto (WKY) rat. The ROS in the NTS of SHR was reduced by losartan. The NO content in the NTS of SHR was lower than WKY, while losartan and tempol could increase NO in the NTS of SHR. Immunoblotting and immunohistochemistry studies demonstrated that Ang II-induced hypertension inhibited neuronal NO synthase (nNOS), ERK and RSK phosphorylation levels in the NTS of SHR. These results suggest that Ang II induces ROS production in the NTS of SHR. In addition, the cardiovascular modulatory effects of Ang II in the NTS are accomplished by downregulation of ERK1/2-RSK phosphorylation levels and then nNOS level.

Chinese Abstract……………………………………………………………………I
English Abstract…………………………………………………………………….III
Abbreviation………………………………………………………………………...V
Contents……………………………………………………………………………..VII

1. Introduction………………………………………………………………………..1
2. Specific Aims……………………………………………………………….……13
3. Materials and Methods……………………………………………………...…....14
4. Results……………………………………………………………………………26
5. Discussion………………………………………………………………………..40
6. Conclusion…………………………………………………………………...…...46
7. Future Perspectives……………………………………………………………47
8. References………………………………………………………………………..49
9. Figures and Figure Legends……………………………………………………59
10. Appendix……………………………………………………………………..…106

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