第一型類胰島素生長因子(IGF-1)被認定為與動脈高血壓形成有關的影響因子，不僅在於具有促生長的作用，而且具有調節血管樞紐的能力。許多研究報告指出，第一型類胰島素生長因子在心血管系統中對於血壓的調節扮演很重要的角色。我們實驗室過去曾經報導，將胰島素微量注射到大鼠的孤立束核(NTS)內，產生血壓下降及心搏舒緩現象，另外也會造成PI3K下游的蛋白激

Insulin-like growth factor 1 (IGF-1) was considered as a factor potentially involved in arterial hypertension because of its effects on vascular tone. Several studies have suggested that IGF-1 might play an important role in the cardiovascular system for regulation of blood pressure. Previously, microinjection of insulin into the NTS of rats preceded prominent depressor and bradycardic and activates the PI3K downstream Akt. The aims of this study was to compare the cardiovascular responses induced by IGF-1 and to investigate the mechanisms of IGF-1induced signaling pathway in the nucleus tractus solitarius (NTS) between spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY) at 8/16 weeks old. The results indicate that microinjection of IGF-1 into the NTS of WKY and SHR produced dramatically depressor and bradycardic effects. The cardiovascular effects evoked by IGF-1 are less in SHR than WKY rats. The defect in IGF-1 vascular action is also present in young spontaneously hypertensive rats (age 8 weeks). Pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 significantly attenuated the responses evoked by microinjection of IGF-1 in both SHR and WKY at 8/16 weeks old. Moreover, mitogen-activated protein kinase kinase (p44/p42MAPK) inhibitor PD98059 administration attenuated the cardiovascular effects of IGF-1 in WKY at 8/16 weeks old but had no effect in SHR at age matched.
In conclusion, both IGF-1/PI3K and p44/p42MAPK signal transduction pathways are involved in controlling central cardiovascular effects in WKY, whereas PI3K but not p44/p42MAPK signaling pathway is involved in SHR. This different condition suggests that such insensitive pathway may play a causative role in the development of hypertension.

Contents
Chinese Abstract……………………………………………………………………. i
English Abstract……………………………………………………………………. iii
Contents…………………………………………………………………………….. v
List of tables………………………………………………………………………... viii
List of figures………………………………………………………………………. ix
Abbreviations………………………………………………………………………. xii

1 Introduction…………………………………………………………………… 1
1.1 IGF-1 and Insulin………………………………………………………………………. 1
1.2 IGF-1 receptor (IGF-1R)………………………………………………………………. 2
1.3 Phosphatidylinositol 3-kinase (PI3K)………………………………………………….. 3
1.4 Mitogen-Activated Protein Kinases (MAPK)………………………………………….. 5
1.5 IGF-1 signaling and central cardiovascular regulation………………..…..……...….… 5
1.6 Cardiovascular regulation of the nucleus tractus solitarii……………………..………. 7
1.7 Spontaneously hypertensive rats (SHR)……………………………………………….. 9
2 Specific Aims..............………………………………………………………… 12
3 Materials and Methods….……………………………………………….…… 14
3.1 Reagents and chemicals……………………………………………………….……… 14
3.2 Animals………………………………………………………………………………... 14
3.3 In vivo studies…………………………………………………………………………. 15
3.3.1 Experimental protocol…………………………………………...………………. 16
3.3.2 Microinjections of drugs………………………………………….……………... 16
3.4 In situ studies………………………………………………………………………….. 17
3.4.1 Immunohistochemisry (IHC)…..…………..………………………….…………. 17
3.5 Protein analysis………………...……………………………………………………... 18
3.5.1 Protein Purification……………………………………………………………... 19
3.5.2 Western blot analysis………………………………………….…….…………... 19
3.5.3 Quantitative analysis of Western blot……………………………….…………... 20
3.6 Statistical Analysis……………………………………………………….……………. 20
4 Results…………………………………………………………………….…… 22
4.1 The cardiovascular effects of IGF-1 microinjection into NTS……………………... 22
4.2 Localization and evaluation IGF-1R in the NTS of WKY and SHR ……………... 22
4.3 PI3K pathway and IGF-1-mediated cardiovascular effects in WKY rats……….... 23
4.3.1 Attenuation of PI3K inhibitor on IGF-1-mediated cardiovascular effects in the NTS of WKY rats……………………..……………….......................................... 23
4.3.2 Induction of Akt phosphorylation by IGF-1 injection into the NTS of WKY rats……................................................................................................................. 24
4.3.3 Attenuation of IGF-1 induced in situ AktSer473 phosphorylation by LY294002 in the NTS of WKY rats…………………………………………………………...... 25
4.4 PI3K pathway and IGF-1-mediated cardiovascular effects in SHR…….………… 26
4.4.1 Attenuation of PI3K inhibitor on IGF-1-mediated cardiovascular effects in the NTS of SHR……………..……………………………………………………….. 26
4.4.2 Induction of Akt phosphorylation by IGF-1 injection into the NTS of SHR ……. 26
4.4.3 Attenuation of IGF-1 induced in situ AktSer473 phosphorylation by LY294002 in the NTS of SHR………………………………………………………………….. 27
4.5 MAPK pathway and IGF-1-mediated cardiovascular effects in WKY rats……… 27
4.5.1 Attenuation of MAPK inhibitor on IGF-1-mediated cardiovascular effects in the NTS of WKY rats…………..………………………….......................................... 28
4.5.2 Induction of ERK1/2 phosphorylation by IGF-1 injection into the NTS of WKY rats……................................................................................................................. 28
4.5.3 Attenuation of IGF-1 induced in situ ERKThr202/Tyr204 phosphorylation by PD98059 in the NTS of WKY rats……………………………………………….. 29
4.6 MAPK pathway and IGF-1-mediated cardiovascular effects in SHR…………….. 30
4.6.1 Attenuation of MAPK inhibitor on IGF-1-mediated cardiovascular effects in the NTS of SHR ……………………………………………………………………... 30
4.6.2 Induction of ERK1/2 phosphorylation by IGF-1 injection into the NTS of SHR... 30
4.6.3 Attenuation of IGF-1 induced in situ ERKThr202/Tyr204 phosphorylation by PD98059 in the NTS of SHR…………………………………………………….. 31
5 Discussion………………………….………………………………………….. 33
6 Conclusion…………………………………………………………………….. 40
7 Future perspectives…………………………………………………………… 41
8 References……………………………………………………………………... 43
9 Appendix………………………………………………………………………. 90

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