動脈血壓之調控為一複雜之生理現象，除血管本身變異會造成調節功能失調引起高血壓外，血液中多種分子與化學物質代謝失調，也是造成高血壓之主因。細胞進行有氧呼吸之代謝副產物超氧陰離子 (superoxide anion, O2-)及過氧化氫 (hydrogen peroxide, H2O2)，在文獻中已有報導，在高血壓狀況下血管壁中此等物質濃度增高，可能與高血壓形成有關。另一方面延腦鼻端網狀腹外側核 (rostral ventrolateral medulla, RVLM)為中樞神經系統調節血壓恆定相當重要的神經核，它可藉由調控交感神經節前神經元之活性，維持血壓恆定，同時此核也參與反射性血壓調節機制，以維持血壓穩定。延腦鼻端網狀腹外側核神經細胞進行有氧代謝製造之超氧陰離子及過氧化氫，在中樞調控心血管功能之研究近期受到重視，然而此等物質在高血壓狀況下延腦鼻端網狀腹外側核參與心血管調節角色之研究，至今仍待進一步探討。
因此本論文假設，過多的超氧陰離子或過氧化氫可在自發性高血壓大鼠 (spontaneously hypertensive rat, SHR)延腦鼻端網狀腹外側核造成過度氧化傷害 (oxidative stress)，導致神經性高血壓的形成。利用成熟雄性自發性高血壓大鼠與正常血壓 (Wistar-Kyoto, WKY)大鼠為實驗材料，首先本研究發現自發性高血壓大鼠延腦鼻端網狀腹外側核區的超氧陰離子含量較WKY大鼠為多，並且過氧化物歧化

Maintenance of a stable arterial blood pressure is a complex physiological phenomenon. In addition to dysfunction of the blood vessels, alterations in homeostasis of circulating signals and humoral factors also contribute significantly to the development of hypertension. Recent evidence indicates that accumulation of the byproducts of cellular respiration, including superoxide anion (O2-) and/or hydrogen peroxide (H2O2), are contributing factors in pathophysiology of hypertension. With respect to the central nervous system, neurons in the rostral ventrolateral medulla (RVLM) play a pivotal role in neural regulation of blood pressure. RVLM neurons not only provide a tonic excitation to maintain the sympathetic vasomotor activity of the blood vessels, they also participate in baroreceptor reflex control of blood pressure. The notion that production of O2- and/or H2O2 in the RVLM participates in central control of blood pressure has recently gained major recognition in the area of hypertension study. Nonetheless, detailed insights into the mechanisms underlying O2- and/or H2O2 promoted hypertension remain to be elucidated.
The hypothesis that forms the basis of this study is that enhanced level of O2- and/or H2O2 in the RVLM may be important factors for the manifestation of hypertension in the spontaneously hypertensive rats (SHR), an animal model of human essential hypertension. In comparison to normotensive Wistar-Kyoto (WKY) rats, basal level of O2- in the RVLM region of adult male SHR rats was significantly higher, along with a reduction in the expression of superoxide dismutase 1 (SOD1), SOD2 or catalase. SOD and catalase are enzymes that metabolize cellular O2- or H2O2 respectively.
Pharmacologically, microinjection bilaterally into the RVLM of SOD mimetic, Tempol (50 nmol) or a pan SOD/calatase mimetic, FeTMPyP (100 nmol), significantly decreased mean systemic arterial pressure (MSAP) or heart rate (HR) in both SHR and WKY rats. The maximal hypotensive effect produced by Tempol or FeTMPyP was significantly greater in SHR than WKY rats. We also found that in SHR, but not WKY rats, the hypotensive and bradycardiac responses after microinjection bilaterally into the RVLM of FeTMPyP was significantly greater than that by Tempol. In addition, infection of RVLM neurons with adenoviral vector encoding SOD1 (Ad-SOD1), SOD2 (Ad-SOD2) or catalase (Ad-Catalase) gene (5x108 pfu) into the bilateral RVLM resulted in a long-term hypotensive effect in SHR but not WKY rats. The temporal profile of Ad-catalase-promoted hypotension was again longer than that promoted by Ad-SOD1 or Ad-SOD2 alone. At the molecular level, gene transfer of SOD1, SOD2 or catalase into the RVLM region of SHR or WKY rats specifically increased the expression of individual protein, resulting in a reduction in O2- level. Together these results suggest that accumulation of O2- and/or H2O2 in the RVLM is involved in the neural mechanism of hypertension in SHR.

頁次
第一章 緒論與文獻回顧 1
第二章 研究動機與目的 11
第三章 實驗材料與方法 14
第四章 實驗結果 23
第五章 討論 30
第六章 結論 42
參考文獻 44
附圖 52

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