背景資料: 中樞調節交感神經血管張力之神經元位於延腦腹外側核
(rostral ventrolateral medulla, RVLM)中，此核為重要的中樞心血管控制中
心。過氧化小體增生活化受體(peroxisome proliferator-activated receptors,
PPARs)致活劑為目前臨床用於治療第二型糖尿病患者之藥物，其藥理作
用為增加體內胰島素的敏感度，繼而促進血糖下降。可是在動物及人體實
驗中發現，PPARγ 亞型致活劑具有降血壓之作用，但是其血壓下降之藥
理機轉仍然未明。本研究探討自發性高血壓大白鼠 (spontaneously
hypertensive rats, SHR)腦部RVLM 的PPARs 表現，在PPARγ 亞型致活劑
rosiglitazone 產生降血壓效應之關係，並探討可能作用機轉。
實驗材料及方法 : 本研究使用12 週大之自發性高血壓大白鼠和同週數之
正常血壓(Wistar Kyoto, WKY)大白鼠。實驗第一週建立實驗動物的基礎血
壓及心跳等數據，待SHR 或WKY 大白鼠於13 週齡時，連續灌食人工合
成之PPARγ 活化體rosiglitazone (80 mg/kg/day)持續7 天，控制組接受生
理食鹽水灌食。在灌食後持續四週測量其血壓及心跳等數據變化。此外，
灌食rosiglitazone 之SHR 大白鼠在第八天時利用立體定位微量注射，將
PPARγ之拮抗劑GW9662 (5 nmol)投予至兩側RVLM 中，記錄其血壓之即
時變化。在另外一組實驗中，SHR 和WKY 在灌食後第八天取出其RVLM
組織，利用western blot 分析過氧化小體增生活化受體表現之變化。最後，
使用鈣離子阻斷劑Amlodipine (16 mg/kg/day)，於SHR 連續灌食七天後進
行RVLM 中過氧化小體增生活化受體蛋白質分析。
實驗結果: 在SHR 連續灌食rosiglitazone 七天後，其平均動脈壓為
139.8±12.6 mmHg 與灌食生理食鹽水控制組159.2±9.9 mmHg 間有顯著的
差異；但在WKY 則其平均動脈壓並無顯著的差異。上述SHR 於灌食
rosiglitazone 後，其血壓下降約維持十天左右。再者，rosiglitazone 灌食對
於SHR 或WKY 的心跳均無影響。另外，SHR 於灌食rosiglitazone 七天
後，雙側RVLM 接受GW9662 後發現，可對rosiglitazone 引起降血壓效
果有顯著恢復現象。在RVLM 中PPAR 各亞型蛋白質定量分析結果發現，
灌食rosiglitazone 後PPARγ及PPARα於RVLM 中之表現有顯著增加，對
WKY 大白鼠RVLM 中PPAR 各亞型表現則無影響。另外於SHR 灌食
amlodipine七天後，其平均動脈壓從164.8±7.7 mmHg 下降至131.8±7.8
mmHg 有顯著的差異，但是在RVLM 中PPARs 異構物之蛋白質表現並無
顯著的變化。
結論: 本研究發現在SHR 灌食rosiglitazone 後，其血壓下降與PPAR 於
RVLM 中的活化有相關。再者，在RVLM 中PPARγ或PPARα蛋白質表現
增加，可能為rosiglitazone 降血壓效果有關。

Background: The rostral ventrolateral medulla (RVLM), location of the
sympathetic premotor neurons, plays a pivotal role in central cardiovascular
regulation. The peroxisome proliferator-activated receptors-γ (PPARγ) agonist
is commonly prescribed for the treatment of type II diabetes mellitus by its
insulin sensitizing ability. Intriguingly, both animal and human studies
revealed that PPARγ agonist also possesses blood pressure lowering effect
although the underlying mechanism is unknown. We designed a study to
evaluate the hypothesis that activation of PPARγ in the RVLM mediates the
blood pressure lowering effect of PPARγ agonist, rosiglitazone.
Materials and Methods: The 12-week spontaneously hypertensive rats (SHR)
and the age-matched normotensive Wistar Kyoto (WKY) rats were used in
this study. Basal systemic arterial pressure (SAP) and heart rate (HR) were
measured for one week, followed by oral administration of a synthetic PPARγ
agonist, rosiglitazone (80 mg/kg/day), or saline for 7 days. The hemodynamic
profile was recorded for 4 weeks post treatment. The role of PPARγ in the
RVLM on blood pressure lowering effect of rosiglitazone was examined by
microinjection bilaterally into the RVLM of the PPARγ antagonist, GW9662
(5 nmol). In a separated series of experiments, the RVLM of SHR or WKY
rats was removed at the end of rosiglitazone or saline treatment. Protein
expression of PPARα, PPARβ/δ or PPARγ in the RVLM was analyzed by
Western blotting. To ascertain that changes in protein expression are not
secondary to perturbation of SAP, expression of PPARs was also examined inSHR that received oral administration of a calcium channel inhibitor,
amlodipine (16 mg/kg/day), for 7 days.
Results: Compared to saline intake, rosiglitazone significantly lowered the
mean SBP (MSBP, 159.2±9.9 mmHg vs. 139.8±12.6 mmHg) in SHR, but not
WKY rats. This blood pressure lowering effect of rosiglitazone in SHR lasted
for at least 10 days post treatment. Rosiglitazone treatment, on the other hand,
had no significant effect on HR in SHR or WKY rats. At the end of 7-day
treatment, microinjection bilaterally into the RVLM of PPARγ antagonist,
GW9662 (5 nmol), significantly reversed the blood pressure lowering effect of
rosiglitazone in SHR. In addition, protein expression of PPARα or PPARγ
was significantly upregulated in the RVLM of the SHR but not WKY rats that
received rosiglitazone treatment. Oral intake of amlodipine (16 mg/kg/day) for
7 days in SHR significantly lowered MSBP (164.8±7.7 mmHg to 131.8±7.8
mmHg), but did not affect protein expression of PPARα, PPARβ/δ or PPARγ
in the RVLM of SHR.
Conclusion: These results suggest that oral administration of rosiglitazone
exerts blood pressure lowering effect via activation of PPARs in the RVLM of
SHR. Moreover, upregulation of PPARα or PPARγ in the RVLM may
underlie the antihypertensive effect of rosiglitazone.

1.Abbreviations 2
2.Abstract
Chinese 3
English 5
3.Introduction 7
4.Materials and method 18
5.Results 24
6.Discussion 27
7.References 35
8.Figures 53

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2. Dreyer C, Kreyt G, Keller H, Givel F, Helftenbein G, Wahli W. Control of
the peroxisomal