臺灣博碩士論文加值系統

中文摘要
血管張力素參與大白鼠孤獨核調控感壓反射反應之研究
根據過去文獻報導以及我們實驗室過去研究的結果，第二型血管張力素(Angiotensin II, Ang II)及第三型血管張力素(Angiotensin III, Ang III)在孤獨核對感壓反射(baroreflex)具有抑制作用。因此，本論文有三個主要目的：(1) 探討AT1及AT2接受器亞型是否參與Ang II及Ang III調控誘發性(evoked)與自發性(spontaneous)感壓反射反應中。(2) Fos蛋白質是否參與在Ang II及Ang III抑制自發性感壓反射的作用中。(3) Ang III經由AT2接受器產生抑制自發性感壓反射是否需要磷酸鹽酵素(phosphatase)活化。實驗是採成熟雄性Sprague-Dawley大白鼠，先以腹腔注射戊巴比妥鈉鹽(pentobarbital sodium, 40 mg/kg, i.p.)麻醉，並以連續靜脈滴注方式補充戊巴比妥鈉鹽(20 mg/kg/h, i.v. infusion)，以維持動物在穩定麻醉狀況下進行實驗。並配合神經藥理、頻譜分析及免疫化學染色等評估方法進行研究。
Ang參與持續性抑制調控誘發性感壓反射反應之探討
雙側微量注射Ang II或Ang III (10, 20或40 pmol)至孤獨核，對於以phenylephrine (5 mg/kg)所引發感壓反射反應之敏感性具有顯著抑制，並呈劑量相關性。Ang II (40 pmol)的抑制作用可被AT1接受器拮抗劑losartan (1.6 nmol)所逆轉，aminopeptidase A 抑制劑amastatin (3.3 nmol)所減少，並部份地受AT2接受器拮抗劑PD 123319 (1.6 nmol)影響，Ang III (40 pmol)的抑制作用卻可為AT1及AT2接受器拮抗劑 (1.6 nmol) 所逆轉。若雙側微量注射losartan (1.6 nmol)或PD-123319 (1.6 nmol)阻斷內生性血管張力素活性，則明顯地增強感壓反射反應。這些實驗結果顯示內生性的Ang II及Ang III可能經由作用在孤獨核上之AT1及AT2接受器，產生持續性抑制調控誘發性感壓反射。其中Ang II之抑制作用，可能有部份是源自於代謝轉換成Ang III產生的。
AT1及AT2接受器亞型參與血管張力素抑制調節自發性感壓反射之探討
本實驗進一步以動脈血壓及心跳速率訊號之交叉頻譜分析(cross-spectral analysis)，評估在正常生理情況下，血壓自然波動所引發的感壓反射，也就是自發性感壓反射。雙側微量注射Ang II或Ang III (5, 10, 20或40 pmol)至孤獨核，有意義地抑制自發性感壓反射，雖然Ang II (10 pmol)的抑制作用可被AT1接受器拮抗劑losartan (1.6 nmol)所逆轉，卻不受AT2接受器拮抗劑PD 123319 (1.6 nmol)影響。而AT1及AT2接受器拮抗劑 (1.6 nmol)卻可顯著地逆轉Ang III (10 pmol)的抑制作用。這些結果顯示Ang II及Ang III對自發性感壓反射亦具抑制性調節作用，且其作用的接受器亞型與誘發性感壓反射相似。
AT1接受器與Fos蛋白質表現參與Ang II抑制性調控自發性感壓反射之探討
雙側微量注射Ang II至孤獨核，有意義地抑制自發性感壓反射反應，並伴隨著Fos蛋白質的表現。而孤獨核神經元上之Fos蛋白質表現會受AT1接受器亞型拮抗劑所阻斷，卻不明顯受AT2接受器亞型拮抗劑所影響。且無論預處理或同時雙側微量注射c-fos antisense oligonucleotide (AS-ODN)皆會阻斷或減弱Ang II在孤獨核上抑制調節自發性感壓反射反應的作用與Fos蛋白質免疫活性表現。由以上結果推論，Ang II可透過AT1接受器亞型誘發孤獨核神經元之Fos蛋白質表現，來參與抑制調控自發性感壓反射反應。
AT1接受器與Fos蛋白質表現及AT2接受器與磷酸鹽酵素活化參與Ang III抑制性調控自發性感壓反射之探討
雙側微量注射Ang III至孤獨核，顯著抑制自發性感壓反射反應，且亦會誘發孤獨核神經元之Fos蛋白質表現。而Fos蛋白質表現同樣亦受AT1接受器亞型拮抗劑所阻斷，卻不明顯受AT2接受器亞型拮抗劑所影響。且無論預處理或同時雙側微量注射c-fos AS-ODN皆會減弱Ang III在孤獨核上抑制自發性感壓反射反應與Fos蛋白質免疫活性表現有關。雙側微量注射AT2接受器亞型致效劑CGP 42112A，亦明顯產生對自發性感壓反射反應的抑制性調節，且此抑制性調節作用可被蛋白質酪胺酸(tyrosine, Tyr)磷酸鹽酵素抑制劑-sodium orthovanadate，及絲胺酸/酥胺酸(serine/threonine, Ser/Thr)磷酸鹽酵素抑制劑-okadaic acid所阻斷。由以上實驗結果可知，Ang III可透過AT1接受器亞型誘發孤獨核神經元Fos蛋白質表現，參與抑制性調控自發性感壓反射反應；此外，亦可透過AT2接受器亞型活化Tyr及Ser/Thr磷酸鹽酵素，參與抑制調節感壓反射。
結論
綜合以上實驗結果，可歸納得四個主要結論：(1) 內生性的Ang II及Ang III可能經由作用在孤獨核上之AT1及AT2接受器，產生持續性抑制調控感壓反射反應。(2) Ang II及Ang III對誘發性與自發性感壓反射，具有相似的調節作用。(3) 孤獨核神經元上之Fos蛋白質，經過AT1接受器，參與在Ang II及Ang III抑制調控自發性感壓反射作用。(4) Tyr及Ser/Thr磷酸鹽酵素，經過AT2接受器，參與在Ang III抑制調節自發性感壓反射作用。

英文摘要
Participation of Angiotensins at the Nucleus Tractus Solitarii in the Modulation of Baroreceptor
Reflex Response in the rat
The present study attempted to decipher the effects of angiotensins at the nucleus tractus solitarii (NTS) on baroreceptor reflex (BRR), the subtype(s) of angiotensin receptors involved, and whether AT1 receptor subtype-mediated expression of Fos protein or AT2 receptor subtype-mediated activation of phosphatases is involved in this process. Experiments were carried out in adult, male Sprague-Dawley rats that were anesthetized with pentobarbital sodium (50 mg/kg, i.p., with 20 mg/kg/h, i.v. infusion supplements).
Tonic inhibitory modulation of evoked baroreceptor reflex response by endogenous angiotensin II and angiotensin III at the nucleus tractus solitarii in the rat
We evaluated the endogenous action of angiotensin II (Ang II) and its active metabolite, angiotensin III (Ang III), at the NTS in the modulation of BRR response, and the subtype of angiotensin receptors involved in this process. Exogenous application of Ang II or Ang III (10, 20 or 40 pmol) by bilateral microinjection into the NTS significantly and dose-dependently suppressed the BRR response evoked by transient hypertension induced by phenylephrine (5 mg/kg, i.v.). The suppressive effect of Ang II (40 pmol) was blunted by the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), attenuated by aminopeptidase A inhibitor, amastatin (3.3 nmol) and partial antagonized by an equimolar dose of non-peptide AT2 receptor antagonist, PD-123319. On the other hand, the depressive action of Ang III (40 pmol) was blunted by both AT1 and AT2 receptor antagonists (1.6 nmol). Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NTS of losartan (1.6 nmol) or PD-123319 (1.6 nmol) elicited an appreciable enhancement of the BRR response. We conclude that, under a physiologic condition, both endogenous Ang II and Ang III may exert a tonic inhibitory modulation on the evoked BRR response by acting on the AT1 and AT2 receptors at the NTS. Furthermore, at least part of the suppressive action of Ang II may result from its metabolic conversion to Ang III.
Participation of AT1 and AT2 receptor subtypes in the inhibitory modulation of spontaneous baroreceptor reflex response by angiotensins at the nucleus tractus solitarii in the rat
We evaluated the modulatory action of Ang II and Ang III at the NTS on the spontaneous BRR response, and the subtype(s) of Ang receptors involved. Bilateral microinjection of Ang II or Ang III (5, 10, 20, or 40 pmol) into the NTS significantly suppressed the spontaneous BRR response, as represented by the magnitude of transfer function between systemic arterial pressure and heart rate signals, with the effect maximized at 10 pmol. Whereas the suppressive effect of Ang II (10 pmol) was reversed by co-administration of the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), but not by the non-peptide AT2 receptor antagonist, PD-123319, both antagonists appreciably reversed the depressive action of Ang III (10 pmol). We conclude that the Ang II and Ang III may exert a inhibitory modulation on the spontaneous BRR response. Whereas the modulatory action of Ang III was exerted via both AT1 and AT2 receptor subtypes, the same action by Ang II engaged only the AT1 receptor subtype at the NTS.
AT1 receptor subtype-mediated expression of Fos protein is involved in the inhibitory modulation of spontaneous baroreceptor reflex response by angiotensin II at the nucleus tractus solitarii in the rat
Our previous work indicated that the inhibitory modulatory action of Ang II at the NTS on spontaneous BRR response is mediated via the AT1 subtype receptors. The present study evaluated the hypothesis that expression of Fos protein at the NTS is involved in this process. Bilateral microinjection of Ang II (10 pmol) into the NTS significantly suppressed the spontaneous BRR response. This was accompanied by the presence of Fos-like immunoreactivity in the NTS. Both the inhibition on spontaneous BRR response and induction of c-fos in NTS neurons elicited by Ang II were discernibly attenuated by pretreatment or co-microinjection with a 15-mer antisense c-fos oligonucleotide (20 pmol). In addition, those two actions of Ang II were reversed by co-administration of the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), but not by the non-peptide AT2 receptor antagonist, PD-123319 (1.6 nmol). We conclude that Fos expression mediated via AT1 receptor subtype may underlie the inhibitory modulation by Ang II at the NTS on the spontaneous BRR response.
AT1 receptor subtype-mediated expression of Fos protein and AT2 receptor subtype-mediated activation of phosphatase are involved in the inhibitory modulation of spontaneous baroreceptor reflex response by angiotensin III at the nucleus tractus solitarii in the rat
Our previous work indicated that the inhibitory modulatory action of Ang III at the NTS on spontaneous BRR response is mediated via both AT1 and AT2 subtype receptors. The present study evaluated the hypothesis that expression of Fos protein via AT1 receptor and activation phosphatase via AT2 receptor at the NTS are involved in this process. Bilateral microinjection of Ang III (10 pmol) into the NTS significantly suppressed the spontaneous BRR response. This was accompanied by the presence of Fos-like immunoreactivity in the NTS. Both the inhibition on spontaneous BRR response and induction of c-fos in NTS neurons elicited by Ang III were discernibly attenuated by pretreatment or co-microinjection with a 15-mer antisense c-fos oligonucleotide (20 pmol). In addition, those two actions of Ang III were reversed by co-administration of losartan (1.6 nmol). Furthermore, the inhibitory effect of Ang III mediated by AT2 subtype receptors is mimicked by CGP 42112A (10 pmol), a AT2 receptor agonist, and blocked by tyrosine phosphatase inhibitor, sodium orthovanadate (5 nmol), and serine/threonine phosphatase inhibitor, okadaic acid (1 pmol). We conclude that Fos expression mediated via AT1 receptor subtype and activation of tyrosine, serine/threonine phosphatase via AT2 receptor subtype may underlie the inhibitory modulation by Ang III at the NTS on the spontaneous BRR response.
Conclusion
Four major conclusions arise from the above observations. First, both endogenous Ang II and Ang III may exert a tonic inhibitory modulation on the BRR response by acting on the AT1 and AT2 receptors at the NTS. Second, Ang II and Ang III exert similar modulatory action on evoked and spontaneous BRR. Third, Fos protein may play an important physiologic role in AT1 receptor-mediated inhibitory modulatory on spontaneous BRR response. Fourth, activation of phosphatase is involved in AT2 receptor-mediated inhibitory modulation on spontaneous BRR response.

封面
目錄
中文摘要
英文摘要
前言
第一部份 文獻回顧及研究目的
第一章 腎性血管張力素系統
第二章 感壓反射
第三章 心血管訊號頻譜分析
第四章 即時先期基因 c-fos
第五章 研究動機與目的
第二部份 實驗材料與方法
第六章 神經藥理、頻譜分析及免疫組織化學法
第三部份 研究結果
第七章 Ang 作用在大白鼠孤獨核之AT及AT接受器亞型參與持續性抑制調控誘發性感歷反射反應之研究
第八章 AT及AT接受器亞型參與大白鼠孤獨核調控自發性感壓反射反應之研究
第九章 AT接受器亞型與 Fos 蛋白質表現參與第二型血管張力在大白鼠孤獨核調控自發性感壓反射反應之研究
第十章 AT接受器亞型與 Fos蛋白質表現及AT接受器亞型與磷酸鹽酵素活化參與第三型血管張力素在大白鼠孤獨核調控自發性感歷反射反應之研究
第十一章 綜合討論
參考文獻
圖表說明

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