胰島素抗性(insulin resistance)在心臟血管疾病的發展中佔有錯綜複雜的角色。胰島素抗性症狀包含高血壓、糖尿病以及肥胖等病因，然而導致高血壓以及胰島素抗性症狀之間的作用機轉並不清楚。胰島素(insulin)在不同型態的細胞中扮演著多種生物功能。由臨床研究中指出，在神經細胞中，胰島素能經由PI3K的活化刺激產生蛋白激酉每Akt。此外，在人類臍靜脈內皮細胞中，經由胰島素刺激所產生的一氧化氮能被PI3K抑制劑wortmannin所抑制。另外，我們也曾經報導在中樞神經系統中，NO能協助調控血壓。本研究主要的目的為探討高血壓以及胰島素抗性症狀之間的作用機轉以及在大鼠孤立束核神經元中，胰島素訊息傳遞分子參與心臟血管調控的作用，我們研究觀察insulin在urethane麻醉的雄性自發性高血壓以及Wistar-kyoto大鼠的孤立束核神經元中，其血壓及心跳的變化作用。在8週以及16週WKY大鼠中，單邊微量注射insulin (100 IU/ml)到孤立束核會產生降血壓與心跳速率的作用。然而，在16週SHR大鼠中，insulin並沒有引起明顯的心臟血管反應。此外，微量注射insulin到8週的SHR (正常血壓)大鼠中，也會產生相似降血壓與心跳速率的作用。在WKY以及8週SHR大鼠中，insulin的這些心臟血管作用會被前處理PI3K的抑制劑LY294002以及一氧化氮合成酉每的抑制劑L-NAME所減弱；相對的，在16週SHR大鼠中，則沒有明顯的抑制作用。此外，insulin在WKY以及SHR大鼠的孤立束核中能引起蛋白激酉每Akt的磷酸化。因此，這些結果顯示insulin-PI3K-Akt-NOS作用機轉參與心臟血管反應在WKY以及8週SHR大鼠(正常血壓)中，但在16週高血壓SHR大鼠，似乎沒有參與其血壓與心跳的調控。實驗結果也推測出在16週自發性高血壓大鼠中，胰島素分子訊息傳遞之缺失也許是導致高血壓的原因之一。

Insulin resistance plays an intricate role in the development of cardiovascular diseases, hypertension is associated with insulin-resistant states such as diabetes and obesity. However, the underlying mechanism to explain the associations between hypertension and insulin resistance is unknown. The insulin exerts various biological effects in different type of cells. Clinical studies have reported that insulin has been shown to stimulate the protein kinase Akt via activation of PI3K in endothelial cells. Furthermore, insulin stimulated production of nitric oxide (NO) is inhibited by wortmannin in human umbilical vein endothelial cells (HUVECs). We also reported previously that NO contributes to the regulation of blood pressure in central nervous system. The aim of this study was to elucidate the potential mechanisms linking hypertension with insulin resistance and whether insulin signaling may involved in cardiovascular regulation in rat NTS neurons, we investigated the cardiovascular effects of insulin in the nucleus tractus solitarii (NTS) of urethane-anesthetized male spontaneous hypertensive rat (SHR) and normotensive Wistar-kyoto rats (WKY). Unilateral microinjection of insulin (100 IU/ml) into the NTS produced prominent depressor and bradycardic effects in 8/16 week-old WKY. However, no significant cardiovascular effects were found in adult SHR (16 week-old) after insulin injection. Furthermore, young SHR (8 week-old) with normal blood pressure showed depressor and bradycardic effects after insulin injection. Pretreatment with PI3K inhibitor LY294002 and NO synthase inhibitor L-NAME into the NTS attenuated the cardiovascular response evoked by insulin in WKY and young SHR but not in adult SHR. Furthermore, insulin induced Akt phosphorylation in-situ in WKY and SHR rats. Thus, these results indicated that insulin-PI3K-Akt-NOS sensitive mechanisms were involved in WKY and young SHR (normotensive) but not in adult SHR (hypertensive). The results also suggested the possible defective insulin signaling may resulted in the development of hypertension in adult SHR.

Index
Pages
Abbreviations...........................I
Abstract in Chinese..... ...............III
Abstract in English.....................V
Contents................................VII

Contents

Chapter 1 General Introduction............................1
1.1 Backgrounds and Significance.......2
1.2 Specific Aims......................11
1.3 References.........................12

Chapter 2 The Cardiovascular Effects of Insulin
in the Nucleus Tractus Solitarii of
Wistar-kyoto Rats............18
2.1 Summary............................19
2.2 Introduction.......................21
2.3 Materials and Methods..............28
2.4 Results............................33
2.5 Discussion.........................36
2.6 References.........................42
2.7 Figures and Figure Legends.........48

Chapter 3 Determinations of Insulin Signaling
in the NTS Neurons of Spontaneously
Hypertensive Rats............63
3.1 Summary............................64
3.2 Introduction.......................65
3.3 Materials and Methods..............69
3.4 Results............................74
3.5 Discussion.........................77
3.6 References.........................82
3.7 Figures and Figure Legends.........86

Chapter 4 Future Perspectives..........98
4.1 References.........................105
4.2 Figure and Legends.................106

Appendix................................108
A-1 Preliminary Results................109
A-2 Experimental Design and Methods....117

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