臺灣博碩士論文加值系統

過去的實驗結果顯示在長期缺氧下腎臟的排泄機能並無明顯的變化，而隱藏其下是與血管或腎功能有關的腎神經或荷爾蒙系統或多或少均有某些程度的變化。我們假設一氧化氮系統亦可能會增強以因應或拮抗某些血管收縮物質作用之增強，如正腎上腺素。首先以免疫染色顯示在大鼠腎臟的皮質與髓質裡幾乎所有的腎小管均有內皮一氧化氮合成?（eNOS）的表現。為探討長期缺氧對腎臟eNOS表現的影響，我們將暴露於正常氧（海平面，SL）與長期缺氧（模擬高度5,500m, 380 torr, HA）四週的鼠腎，做西方漬點分析與腎功能的研究以比較兩者的差異。西方漬點方法，正常大鼠腎臟髓質中eNOS的含量比皮質的含量高出許多；而eNOS蛋白質在皮質絨毛膜囊的純化過程中逐漸增加。
比較兩組皮質絨毛膜囊與髓質均質液裡eNOS蛋白質的含量，HA組均有顯著地增加。HA鼠血漿中亞硝酸鹽／硝酸鹽的基準量也是顯著地較高，但是對靜脈輸注L-精胺酸（L-arginine）的反應卻不明顯，或許是因腎臟的排泄量增加較巨之故。腎動脈內輸注N-硝基-L-精胺酸甲酯（N-nitro-L-arginine methyl ester, L-NAME）會減少腎臟血行動力（腎絲球過濾率和腎皮質微血管血流）和腎臟排泄（尿量和尿鈉），而HA組也有比較快捷與劇烈的反應。這些發現顯示：一、eNOS是有表現於近端腎小管的絨毛膜上；二、長期缺氧腎臟eNOS的表現與NO在腎臟中的作用均有增強的跡象。此NO/NOS系統的增強，應是扮演拮抗在長期缺氧中所增強的血管收縮物質或腎臟交感神經活動度的角色。
過去的結果顯示長期缺氧鼠腎臟中正腎上腺素的含量比較高，但其腎功能並未有變化。而一氧化氮正可抑制正腎上腺素在腎臟的血管收縮與抗利尿作用。我們假設長期缺氧下腎臟對正腎上腺素的反應可能已有改變或是有牽涉一氧化氮的可能。我們發現在靜脈輸注正腎上腺素（300 mg/kg/h）時，HA組有相同的血壓上升但其利尿與利鈉比較差；以機械方式提升動脈壓時，HA組的壓力利尿並未有明顯的差別。在腎動脈內直接輸注正腎上腺素（10 mg/kg/h）會減少腎血流、腎絲球過濾率、皮質微血管血流、尿量、尿鈉、尿鉀等，HA組的減少比較明顯。在HA鼠，先腎動脈內輸注L-精胺酸（100 mg/kg/h）再由靜脈輸注正腎上腺素（300 mg/kg/h），並未改變正腎上腺素在腎臟的作用；若先腎動脈內輸注phosphoramidon（100mg/kg/h）時，卻可增強正腎上腺素在腎臟的作用，使其利尿與利鈉反應與SL鼠幾乎相同。這些結果顯示在長期缺氧腎臟中正腎上腺素的過度作用上，NO系統的拮抗角色並不明顯；而可能是在腎臟中某些抗利尿/抗利鈉因子作用過度或是利尿/利鈉因子作用不足，故仍須進一步的研究。
在大鼠腰部熱敷會產生明顯利尿的現象，但其作用機轉尚未全然清楚。我們利用一電加熱板（42℃）在腎臟部位的背部皮膚上面熱敷，來探討腎神經、腎臟感覺接受器及NO在腰部熱敷中腎功能調節的角色。我們發現腎神經完整組在腰部熱敷時，腎臟輸出神經活動度和腎臟傳入神經活動度均有減少，並伴有尿量、尿鈉、尿鉀排泄與腎絲球過濾率的增加。但在慢性腎神經切除組，發現其反應與腎神經完整組幾乎相同。為解釋腎臟傳入神經的活動度在腰部熱敷中會減弱，接著探討腎臟知覺接受器是否受腰部熱敷的影響。在腰部熱敷時，腎臟R2化學性接受器（CR2）的活動度會顯著地減少，而三種機械性接受器的活動度則未有變化；腎臟血行動力與排泄的增加，可能沖淡腎臟裡的一些化學物質，以致減少腎臟內化學性接受器（CR2）的放電速率；而CR2的減少，除可造成RANA的減少外，並可經反射連帶地使RENA減少。而腰部熱敷時，尿中亞硝酸鹽／硝酸鹽總量未有顯著的增加，表示NO系統在腰部熱敷中並未有明顯的角色。
總結，長期缺氧下，腎臟的NO/NOS系統有增強的表現與作用；同時正腎上腺素在腎臟的直接作用比較過度，且腎臟內的正腎上腺素有增加的跡象（Chien et al, 1995）；然而在正腎上腺素在腎臟的過度作用中，未見NO有明顯參予的跡象。在腰部熱敷中，腎神經或腎臟化學接受器的活動度雖有減少，但腎神經的切除證明此二者顯然並非是其腎臟排泄增加的主要作用者，而似乎有體液因子涉入之可能，但NO不是其中的主要者。

Previous data showed that renal function is not altered in chronic hypoxia. However, the underlying neural or hormone system which has vasoactive or renal action has been changed more or less to a certain degree. We hypothesized that nitric oxide (NO) system might be activated in response to the augmented vasoconstrictors, such as norepinephrine. The first part of this thesis was focused on the role of NO in chronic hypoxia. By immunohistochemistry, the immunoreactivity of endothelial nitric oxide synthase (eNOS) was localized in almost all tubules of rat renal cortex and medulla. To explore the effect of chronic hypoxia upon renal NO/NOS system, Western blot analysis and renal functional study were compared in the kidneys of rats exposed to normoxia (sea level, SL) and chronic hypoxia (simulated high altitude 5,500 m, 380 torr, HA) for 4 weeks. By Western blot, abundant eNOS was present in the medullary homogenates while eNOS was enriched in the cortical brush border membrane vesicles (CBBMV) purified from renal cortex. The renal eNOS in CBBMV and medullary homogenate was increased significantly in the HA groups. The basal level of plasma nitrite/nitrate was higher in HA rats but remained unresponsive to intravenous L-arginine loading with greater renal excretion. Coincidentally, intrarenal arterial infusion of N-nitro-L-arginine methyl ester (L-NAME) also elicited more prompt and susceptible decline of renal hemodynamics and urinary sodium excretion in HA rats. These findings suggest that eNOS is present in renal brush border membrane. In chronically hypoxia, the expression of renal eNOS and the intrarenal NO activity is enhanced. The augmented NO/NOS system might play a role in counteracting the enhanced vasocon-strictive hormone and/or renal sympathetic tone after chronic hypoxia.
Based on the facts that the renal excretion is not altered in spite of higher norepinephrine (NE) content in chronically hypoxic kidneys and NO inhibits norepinephrine-induced renal vasoconstriction and antidiuresis. We hypothe-sized that renal response to NE might be altered or NO system might be involved. With a similar vasopressor effect, attenuated diuresis/natriuresis was shown in HA rats during systemic infusion of NE (300 mg/kg/hr, i.v.) but no difference in the pressure diuresis/natriuresis induced by mechanical ligation. The decline of renal function was more exaggerated in HA rats during intrarenal artery infusion of NE (10 mg/kg/hr). In HA rats, the pretreatment with L-arginine (100 mg/kg/h, i.r.a.) did not alter the renal effect of NE (300 mg/kg/hr, i.v.). However, the attenuated diuresis/natriuresis responded to the pretreatment with phosphoramidon (100 mg/kg/hr, i.r.a.) and the diuresis/natriuresis increased to the level as that seen in SL rats. These results suggest that the kidney is more susceptible to NE in chronic hypoxia. The contributing intrarenal factor seems to be either an insufficient diuretic/natriuretic factors or an exaggerated antidi-uretic/antinatriuretic factors instead of NO.
Back heating enhanced renal excretion but the mechanism is not known. To investigate the role of renal nerve, renal sensory receptor and NO in the enhancement, we applied an electric heating pad (42 oC) on the back skin overlying the rat kidneys. During back heating, both renal afferent (RANA) and efferent (RENA) nervous activity were reduced with increased urinary excretion and glomerular filtration rate in renal nerve intact rats. Chronic bilateral renal denervated rat failed to alter the enhanced renal response. To explain the decline of RANA, we investigated which renal sensory receptor is involved. CR2 activity was significantly decreased during and after BH, but all three other types of MRs did not alter. It seemed that the enhanced renal excretion dilutes some chemicals in the kidney to decrease the firing rate of CR2 chemoreceptors. The decrease in CR2 activity accounts for the decreased RANA and might lessen RENA via reflex. During back heating, the urinary nitrite/nitrate level didnot increase significantly, implying no major role of NO system.
Chronically hypoxic kidneys are shown to have enhanced intrarenal action and expression of NO/NOS as well as exaggerated renal response to NE with higher intrarenal NE content. In the latter exaggerated response, the role of NO is not evident. In back heating, the decreased activity of renal nerve and chemoreceptor was not acting as the main effector of the enhanced excretion as it failed to alter by renal denervation. Probably it seems that some humoral factors might be involved but NO is not the major one.

目 錄： 頁
封 面 I
審定書 II
致 謝 III
目 錄 IV
表 次 VII
圖 次 VIII
中文摘要 X
英文摘要 XIII
第一章 緒論
1-1 長期缺氧中腎臟之生理變化 1
1-2 長期缺氧與正腎上腺素 5
1-3 長期缺氧與一氧化氮合成? 7
1-4 熱敷（Back Heating） 12
1-5 實驗目的 16
第二章 長期缺氧增強腎臟內皮一氧化氮合成?的表現與一氧化氮的作用
2-1 前 言 17
2-2 材料及方法 18
2-3 結 果 23
2-4 討 論 25
第三章 長期缺氧中正腎上腺素減弱腎臟的排泄及一氧化氮的角色
3-1 前 言 36
3-2 材料及方法 37
3-3 結 果 39
3-4 討 論 40
第四章 腰部熱敷後腎神經、腎臟感覺接受器與一氧化氮的角色
4-1 前 言 51
4-2 材料及方法 52
4-3 結 果 56
4-4 討 論 57
第五章 結 論 66
第六章 參考文獻 67
第七章 附錄 生物醫學年會摘要 90

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