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研究生:黃正義
研究生(外文):Cheng-Yi Huang
論文名稱:ProstaglandinI2參與大白鼠孤獨核調控感壓反射之研究
論文名稱(外文):Modulation of Baroreflex Response by Prostaglandin I2 in the Nucleus Tractus Solitarii of the Rat
指導教授:嚴錦城
指導教授(外文):Jiin-Cherng Yen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:孤獨核前列腺素感壓反射
外文關鍵詞:NTSprostaglandinBRR
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Prostaglandin I2 (PGI2),是花生四烯酸(arachidonic acid) 之代謝產物,具有明顯舒張血管及抑制血小板凝集作用。早期的研究指出血管的內皮細胞是合成PGI2的主要場所;然而,近期的文獻則顯示PGI2也可能在中樞神經系統被合成。
在中樞神經系統中,孤獨核(nucleus tractus solitarii) 是掌管心血管功能的感壓反射路徑上最重要的整合核區之一,目前已知孤獨核中也有PGI2的接受器及環氧酶(cyclooxygenase) 的存在,因此,PGI2可能在孤獨核調控心血管功能方面扮演重要的生理角色。然而,孤獨核中是否存在PGI2合成酶(PGI2 synthase; PGIS),目前仍是未知,因此本研究為了釐清孤獨核中PGIS的分佈,進行免疫組織染色(immunohistochemical staining),由實驗結果可以得知,PGIS大量在孤獨核背側區表現,雙重染色實驗更進一步發現PGIS是存在於表現NMDA接受器或AMPA接受器的神經細胞中。此外,孤獨核中內生性PGI2之生理角色仍屬未知,因此本研究亦進一步雙側微量注射PGIS抑制劑至孤獨核,結果顯示孤獨核背側區內生性PGI2則使感壓反射反應降低,而在孤獨核腹側區內生性PGI2導致感壓反射反應增加;此外雙側微量注射PGI2類似物iloprost至孤獨核背側區,也會造成感壓反射反應降低;而雙側微量注射iloprost至腹側區則使感壓反射反應增加。若將iloprost及nictric oxide synthase (NOS) 抑制劑共同微量注射至孤獨核腹側區,結果顯示非選擇性NOS抑制劑L-NAME及neuronal NOS (nNOS) 抑制劑vinyl-L-NIO會阻斷iloprost增加感壓反射反應之作用,然而,endothelial NOS抑制劑L-NIO則對iloprost增加感壓反射反應之現象沒有影響,由此可知iloprost造成感壓反射反應增加之作用,可能是透過活化孤獨核中nNOS而來。此外,為了釐清iloprost引起感壓反射反應增加現象是否藉由影響交感
神經系統或副交感神經系統所造成,因此預處理ipratropium (週邊muscarinic 接受器抑制劑) 或atenolol (週邊β-adrenoceptor抑制劑),結果發現ipratropium能夠阻斷iloprost所造成感壓反射反應增加之現象;而atenolol則只能在投與iloprost後三十分鐘內,產生抑制作用,即iloprost促進感壓反射反應主要是透過活化副交感神經而來。
綜合而言,本研究發現PGI2在孤獨核背側區扮演抑制感壓反射反應之角色;而在孤獨核腹側區則是增加感壓反射反應的角色。其作用可能是透過活化nNOS產生NO,進而使得週邊副交感神經活性增加,造成感壓反射反應增加之現象。
Prostaglandin I2 (PGI2), derived from arachidonate metabolites, which exerts the potent ability in vasodilation and anti-platelet aggregation. During the past decades, numerous studies have suggested that PGI2 is produced mainly in the vascular endothelium. Further, recent evidence indicated that PGI2 could also be produced in central nervous system. Nucleus tractus solitarii (NTS), the primary terminal site of baroreceptor afferents, plays a principal role in the baroreceptor reflex (BRR) response. Besides, previous studies evidenced that cyclooxygenase (COX) and PGI2 receptor are located in NTS. However, the physiological role of PGI2 in NTS is still unclear. In the present study, immunhistochemical staining illustrates that the PGI2 synthase (PGIS) is abundant expressed in NTS, co-localized with neuronal nucleus protein (NeuN) and ionotropic glutamate receptors. Furthermore, bilateral microinjection with PGIS inhibitors in dorsal NTS enhanced the BRR response but suppressed response exhibits in ventral NTS. Bilateral microinjection of iloprost (a stable analogue of PGI2) significantly suppressed the BRR response in dorsal NTS. Inversely, microinjections of iloprost into ventral NTS enhanced the BRR response. On the other hand, the enhanced BRR response caused by iloprost was attenuated by co-microinjection with the non-selective nitric oxide synthase (NOS) inhibitor or neuronal nitric oxide synthase (nNOS) inhibitor in ventral NTS. The promotional effects of iloprost on the BRR response was completely abolished by microinjection of ipratropium (the peripheral muscarinic blocker), but showing no effects by microinjection of atenolol (the peripheral β-adrenoceptors blocker). These results together suggest that endogenous PGI2 in
the dorsal NTS may play a suppressive role in BRR response, and iloprost may play a modulatory role in the BRR response via a central nitric oxide dependent vagal nerve mechanism.
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