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研究生:翁汶燦
研究生(外文):Wen-Tsan Weng
論文名稱:alpha-MSH在自發性高血壓老鼠孤立束核中的心血管作用
論文名稱(外文):The Cardiovascular Effects of alpha-Melanocyte-Stimulating Hormone in the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats
指導教授:戴明泓曾清俊曾清俊引用關係
指導教授(外文):Ming-Hong TaiChing-Jiunn Tseng
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物醫學科學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:英文
論文頁數:70
中文關鍵詞:孤立束核自發性高血壓老鼠心血管作用一氧化氮
外文關鍵詞:spontaneously hypertensive rats (SHR)nucleus tractus solitarii (NTS)depressor and bradycardic effectsnitric oxide (NO)melanocortin receptorcardiovascular effectalpha-melanocyte stimulating hormone
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alpha-melanocyte-stimulating hormone (alpha-MSH) 在食慾、代謝速率與免疫方面被認為是個重要的調節因子。最近更有文獻指出,alpha-MSH也會影響交感神經的活性與血壓的調控。在本研究中,我們利用微量注射的方式將alpha-MSH注射入自發性高血壓老鼠 (spontaneously hypertensive rats,SHR) 的孤立束核 (nucleus the tractus solitarii,NTS) 中,探討alpha-MSH所產生的心血管調控作用;同時,由於目前已知一氧化氮和心血管調控有密切的關聯,因此我們也將更進一步探討alpha-MSH對心血管調控產生的作用是否與一氧化氮的調控機制相關。在麻醉狀態下的自發性高血壓老鼠,利用單邊微量注射alpha-MSH (0.3~300 pmol) 到孤立束核內會引起血壓下降與心跳的減緩,且呈現顯著的劑量效應;而此降血壓與減緩心跳的作用會被melanocortin 3/4-receptor的拮抗劑,SHU9119,抑制。注射一氧化氮的前趨物L-arginine做前處理,能使得alpha-MSH所產生的降血壓與減緩心跳的作用時間增長;相反地,一氧化氮合成酶的抑制劑L-NAME (N-nitro-L-arginine methyl ester),則會抑制alpha-MSH產生的降血壓作用。接著利用誘導性一氧化氮合成酶 (inducible nitric oxide synthase) 的抑制劑aminoguanidine (AG),可明顯觀察出AG能抑制alpha-MSH在心血管調控上的作用;而神經性一氧化氮合成酶 (neuronal nitric oxide synthase) 抑制劑7-nitroindazole,則無此效應。因此我們推測注射alpha-MSH於自發性高血壓老鼠的孤立束核中具有降血壓與減緩心跳的作用,而此機制似乎是藉由melanocortin 4-receptor訊息機轉進而活化一氧化氮合成酶,使其進而在孤立束核產生一氧化氮而達到心血管調控作用。
alpha-melanocyte stimulating hormone (alpha-MSH) is an important regulator of food intake, metabolic rate, and inflammation. Recently, alpha-MSH was shown to influence sympathetic activity and blood pressure regulation. In the present study, we investigated the cardiovascular effects of alpha-MSH in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHR). Because nitric oxide (NO) is well-known to involve in central cardiovascular regulation, we elucidated the role of NO in the cardiovascular responses induced by alpha-MSH. In urethane-anesthetized SHR, unilateral microinjection of alpha-MSH (0.3-300 pmol) into the NTS produced dose-responsive depressor and bradycardic effects. The cardiovascular effects of alpha-MSH were abrogated by the antagonist of melanocortin receptor (MC3/4-R), SHU9119. Pretreatment with precursor of nitric oxide, L-arginine, enhanced the duration of alpha-MSH-mediated hypotensive effects, whereas prior application of L-NAME, a universal inhibitor of nitric oxide synthase (NOS), significantly attenuated the effects of alpha-MSH. Prior injection with inhibitor of inducible NOS, aminoguanidine, but not inhibitor of neuronal NOS, 7-nitroindazole, attenuated the hypotensive effect of alpha-MSH. In summary, these results indicated alpha-MSH induced depressor and bradycardic effects in the NTS of SHR. Besides, the hypotensive mechanism of alpha-MSH was mediated via MC4-R and involved with iNOS activation in the NTS of SHR.
Pages
Contents ⅰ
Abstract in Chinese iv
Abstract in English vi
Abbreviations vii

Introduction
Pro-opiomelanocortin (POMC)………………………………1
POMC-derived neuropeptides………………………………2
Melanocortin receptors…………………………………………………2
alpha-melanocyte-stimulating hormone (alpha-MSH)………3
Nitric oxide (NO)………………………………………………4
Cardiovascular effects of NO in the NTS…………………6
Hypertensive animal models…………………………………8
Specific aims……………………………………………………9

Methods and Materials
Animals...............................................10
NTS microinjection....................................10
Cell cultures.........................................13
Western blot analysis.................................13
Immunohistochemical staining..........................14
Statistical analysis..................................15

Results
Microinjection of alpha-MSH into the NTS caused dose-responsive hypotension in SHR and WKY rats..........16
Antagonist of MC3/4-R, SHU9119, inhibited the cardio-vascular effects of alpha-MSH effectively in SHR and WKY rats................................................16
NO pathway participated in alpha-MSH-induced cardio-vascular effects in SHR and WKY rats..................17
iNOS is involved in the cardiovascular effects of alpha-MSH................................................18
PKA inhibitor, H89, abolished the cardiovascular effects of alpha-MSH in SHR................................19
iNOS was co-localized with MC4-R in the NTS of SHR and WKY rats................................................19

Discussion..........................................20

Future Perspectives.................................24

References..........................................26

Tables...............................................34

Figures..............................................36
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