臺灣博碩士論文加值系統

長期暴露於間歇性低氧之環境，如同睡眠呼吸中止病患於睡眠期間處於反覆性呼吸中止現象，可能進而導致高血壓。高血壓患者亦有較高比率罹患睡眠呼吸中止症。此外，間歇性低氧狀況如同發生缺氧後再給予氧氣供應，可增加細胞中反應性氧衍生物之釋放量，特別是超氧陰離子。在本實驗中，我們推測間歇性低氧會導致自發性高血壓動物動脈化學反射增強，進而引發嚴重的心肺功能失調。臨床及動物實驗的研究指出，高血壓患者和動物其體內常伴隨著較高的氧化壓力。因此，本實驗將探討清醒自發性高血壓大鼠暴露於間歇性低氧時，其動脈化學反射敏感性、自主神經活性與動脈血壓變化，假如可造成其變化時，進而著重於內生性的反應性氧衍生物是否參與於這些心肺功能反應過程中。本實驗採用八至九週大之成熟雄性自發性高血壓大鼠，每天於動物光亮期暴露於間歇性低氧或正常空氣環境，間歇性低氧之周期為75秒/次（灌流30秒的氮氣後，再予灌流45秒的空氣)，每天持續六小時，連續觀察三十天。實驗過程中，使用非侵入性無線遙測儀偵測每天動脈血壓訊號，並將此動脈血壓訊號再經由平均動脈血壓以及心率變異性分析，用以評估自主神經功能之活性。利用小動物體積描記系統，每天測量清醒動物於空氣及急性低氧（12% O2）下，其大鼠呼吸速率、潮氣容積、每分鐘肺通氣量等化學反射之基礎值。我們發現間歇性低氧組其心臟交感神經活性指標、交感神經血管運動調控指標以及血壓皆有明顯上升的趨勢，而空氣組僅有些微上升。同樣地，間歇性低氧組在正常空氣刺激下之每分鐘肺通氣量亦有明顯增加。然而，在心臟副交感神經活性指標以及心跳速率部分，兩組之間並無明顯差異。而事先以腹腔注射之方式給予10 mg/kg超氧陰離子驅除物，則可有效抑制間歇性低氧所引發之血壓上升、交感神經活性增強以及每分鐘肺通氣量增加反應。根據上述結果，可間接推測長期間歇性低氧所引發之血壓上升現象與化學反射反應增強及交感神經活性上升有關，而超氧陰離子可能參與於間歇性低氧所引發之上述增強反應中。

Chronic intermittent hypoxia (CIH), such as that occurring in association with sleep apnea, may result in systemic hypertension. Importantly, sleep apnea occurs frequently in the hypertensive patients. Intermittent hypoxia seems to resemble hypoxia-reoxygenation, wherein cellular generation of reactive oxygen species, especially superoxide anion is increased during reoxygenation. In this study, we proposed that intermittent hypoxia (IH) induced exaggerated arterial chemoreflex sensitivity in hypertensive subjects, and further contribute to development of impaired cardiorespiratory responses. Evidence from human and animal studies has shown that the increased oxidative stress was present in different models of hypertension. Therefore, we investigated whether IH challenge affects arterial chemoreflex sensitivity, autonomic function, and arterial blood pressure and, if so, determine the role of ROS involves in eliciting these cardiopulmonary alternations in conscious unrestrained spontaneously hypertensive rats (SHRs). We used age-matched (8-9-wk-old) adult male SHRs exposed to repetitive 1.25-min cycles (30 s of N2 + 45 s of 21% O2) of IH or room air (RA) for 6 h/day during light phase (10 AM-4 PM) for 30 days. Blood pressure signals were measured daily by the telemetry system, which were used to assess the autonomic function by mean arterial pressure and heart rate variability analysis. Respiratory responses during room air (RA) breathing and acute hypoxia (12% O2), the indices for tonic and phasic chemoreflex sensitivity, respectively, were measured daily using the barometric technique of plethysmography. We found that IH markedly increased the normalized low-frequency power of pulses interval spectrogram (LF%) (an index for cardiac sympathetic), low-frequency power of the MAP spectrogram (BLF) (an index for sympathetic vasomotor activity) and mean arterial pressure in SHRs, whereas RA evoked only a mild elevation of these responses. Similarly, IH challenge exhibited significant increases in minute ventilation by breathing RA. However, no significant differences in high-frequency power of pulses interval spectrogram (HF) (an index for cardiac vagal activity) and heart rate were observed between these two groups. Pretreatment with a superoxide anion scavenger (MnTMPyP, 10 mg/kg, i.p.) totally prevented CIH-induced the hypertensive response and minute ventilation in breathing RA. These results suggest that exaggerated blood pressure response to intermittent hypoxia may be associate with arterial chemoreflex activations and facilitation of sympathetic outflow in conscious SHRs, and superoxide anion may involve in CIH-induced these cardiorespiratory responses.

目錄--------------------------------------------------------------------------------------------------------------I
中文摘要------------------------------------------------------------------------------------------------------III
英文摘要-------------------------------------------------------------------------------------------------------V
壹、緒言
重要性-----------------------------------------------------------------------------------------------------1
背景知識
一、長期間歇性低氧對生理之影響--------------------------------------------------------------3
二、長期間歇性低氧引發週邊化學反射反應之變化-----------------------------------------5
三、間歇性低氧對自主神經功能之影響--------------------------------------------------------7
四、反應性氧衍生物參與於長期間歇性低氧中之變化--------------------------------------8
五、反應性氧衍生物參與於長期間歇性低氧所引發心血管反應過程之可能性-------10
六、高血壓導致睡眠呼吸中止增加之可能原因----------------------------------------------10
七、研究目的----------------------------------------------------------------------------------------11
貳、實驗材料與方法
一、實驗動物-------------------------------------------------------------------------------------------13
二、血壓訊號無線遙測器之埋設手術-------------------------------------------------------------13
三、間歇性低氧模式----------------------------------------------------------------------------------14
四、正常氧分壓模式----------------------------------------------------------------------------------14
五、血壓之測量----------------------------------------------------------------------------------------14
六、自主神經功能之分析----------------------------------------------------------------------------15
七、週邊化學反射反應之測量----------------------------------------------------------------------16
八、代謝速率之測量----------------------------------------------------------------------------------17
九、肺組織脂質過氧化反應之測定----------------------------------------------------------------17
十、藥品-------------------------------------------------------------------------------------------------18
十一、實驗設計及步驟-------------------------------------------------------------------------------19
十二、統計分析----------------------------------------------------------------------------------------20
?礡B實驗結果
一、長期間歇性低氧暴露對大鼠其化學反射反應之影響-------------------------------------21
二、長期間歇性低氧暴露對大鼠其心血管反應之影響----------------------------------------24
三、大鼠於長期間歇性低氧暴露下，肺組織脂質過氧化情形-------------------------------28
四、代謝速率-------------------------------------------------------------------------------------------29
肆、討論-------------------------------------------------------------------------------------------------------30
伍、圖表與說明----------------------------------------------------------------------------------------------38
陸、參考文獻-------------------------------------------------------------------------------------------------70

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