過氧化增生活化受體 (peroxisome proliferator activated receptors, PPARs) 為一群因受體興奮後誘發活化之轉錄因子，已證實參與血糖恆定與脂肪代謝過程。近期研究發現具有降高血壓作用，但造成此一作用之機轉並不明瞭。過去實驗室研究成果顯示，位於延腦鼻端腹外側核區 (rostral ventrolateral medulla, RVLM) 控制中樞交感神經輸出之神經細胞，會因為細胞含有較高含量之超氧陰離子 (superoxide anion, Ο2•−)，造成氧化傷害 (oxidative stress)，而導致交感神經血管活性增強及高血壓表徵。
因此本論文假設，在延腦鼻端腹外側核區，活化過氧化增生活化受體，藉由減緩細胞氧化傷害，在高血壓狀況下可產生降血壓效果。研究以成熟雄性自發性高血壓大鼠 (spontaneously hypertensive rats, SHR) 與正常血壓 (normotensive Wistar-Kyoto, WKY) 大鼠為實驗動物，利用微量注射方式將過氧化增生活化受體致活劑 (PPARγ agonist) Rosiglitazone (1 nmol) 給予到雙側延腦鼻端腹外側核區，發現給藥 後，在SHR 或WKY 大鼠均可造成平均動脈血壓及心跳下降，並且 SHR 下降的幅度大於WKY 大鼠。此外，降血壓的同時也伴隨著 RVLM 細胞內的超氧陰離子含量減少和抗氧化物解偶聯蛋白質 (uncoupling protein, UCPs) 的正向調節。相較於WKY 大鼠，實驗結果發現Rosiglitazone 在SHR 延腦鼻端腹外側核區對上述兩種現象之影響顯著加強。在PPARγ 蛋白質表現方面，給予Rosiglitazone 後SHR 之PPARγ 蛋白質也顯著比WKY 大鼠含量增高。另一方面，利用合併給予PPARγ 致活劑與拮抗劑GW9662 (5 nmol) 之實驗結果顯示，平均動脈血壓有回升之情形，因此GW9662 對於Rosiglitazone 具有可逆作用。綜合上述的結果，我們推論過氧化增生活化受體參與延腦鼻端腹外側核區之降血壓及心跳作用，是經由抑制超氧陰離子產生和增加抗氧化功能之UCPs 表現。因此，在延腦鼻端腹外側核區PPARγ含量減少可能與神經性高血壓有相關性。

Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor family that act as transcription factors to regulate target gene expression. In addition to their well-known effects in regulation of glucose homeostasis and lipid metabolism, PPAR activators have recently been shown to exert antihypertensive effects, although the underlying mechanism is not clear. Our laboratory has previously demonstrated that oxidative stress of an augmented tissue level of superoxide anion (Ο2•−) in the rostral ventrolateral medulla (RVLM), where promotor neurons for generation of sympathetic vasomotor outflow reside, contributes to neural mechanism of hypertension. I therefore propose to test in my thesis the hypothesis that protection against oxidative stress after activation of the PPARs in the RVLM may contribute to the antihypertensive effect of these transcription factors.
Experiments were performed in the spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) rats under anesthesia or conscious condition. Compared to WKY rats, microinjection bilaterally into the RVLM of a synthetic activator of PPARγ, rosiglitazone (1 nmol), evoked significantly greater decreased in mean systemic arterial pressure (MSAP) and heart rate (HR) in SHR. These cardiovascular suppressive
effects of rosiglitazone were accompanied by greater decrease in tissue level of O2
- and upregulation of the antioxidant uncoupling proteins (UCPs) in the RVLM of SHR. Rosiglitazone also caused a significant greater increase in PPARγ expression in the nuclear extracts from RVLM of SHR than WKY rats. All these cellular events induced by rosiglitazone were antagonized by co-administration into the RVLM of the PPARγ inhibitor, GW9662 (5 nmol). This PPARγ inhibitor also significantly reversed the cardiovascular depressive effects of rosiglitazone. Together these results suggest that PPARγ in the RVLM may participate in central cardiovascular regulation by promoting hypotension and bradycardia via amelioration of O2- production and upregulation of antioxidant UCPs. Moreover, a downregulation of the PPARγ in the RVLM may contribute to neural mechanism of hypertension.

正文目錄

頁次
第一章 緒論與文獻回顧 1
第二章 研究動機與目的 24
第三章 實驗材料和方法 28
第四章 實驗結果 40
第五章 討論 48
第六章 結論 60
第七章 未來研究方向 62
參考文獻 65
附圖 81

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