臺灣博碩士論文加值系統

前言 (1).許多學者在不同文獻中都已報導intracellular pH（pHi）的變化對細胞功能的調節扮演著非常重要的角色，例如細胞間偶合能力，細胞膜上離子的通透性等，目前在天竺鼠的心臟細胞上已被證實有五種pHi regulators，共同維持心臟細胞pHi之恆定，包括Na+/H+ exchanger( NHE )、Na+/HCO3- symporter ( NHS )、Cl-/ HCO3- exchanger ( AE ) 、Cl-/ H+ exchanger ( CHE ) 和Lactate-/ H+ symporter ( LHS ) 。 另外也有學者報導pHi regulators在某些病理的現象也扮演很重要的角色，例如在ischemia / reperfusion injury中之NHE的調節作用，人類心臟細胞中負責排酸之pHi regulators已被研究，但目前沒有任何探討有關人類心臟排鹼之pHi regulators的文獻報導。(2).抗心律不整藥主要分四大類（class I ~ class IV），quinidine為class I的抗心律不整藥，主要是透過抑制Na+ channel 的作用來治療心律不整，amiodarone (CORDARONE)為classⅢ的抗心律不整藥，具有抑制K+ channel、Na+ channel、Ca2+ channel和adrenergic blocking 的作用，而去氫吳茱萸鹼( dehydroevodiamine；DeHE )是從傳統中藥吳茱萸分離純化出來的,也已證實具classⅢ的抗心律不整藥的特性（抑制K+ channel），但是quinidine、amiodarone和DeHE對心臟的pHi regulators之NHE的作用，目前沒有任何文獻報導。
實驗目的 本研究主要是(1).探討人類心臟組織之排鹼機轉。(2).探討常用之抗心律不整用藥（quinidine、amiodarone）和研發中之傳統中藥有效成份（DeHE）對人類心臟組織NHE之影響。
材料與方法 (1).實驗標本來源與處理：主要與三軍總醫院之心臟外科合作，於開心手術中剪下之廢棄心房組織，取出小樑肌(trabecular muscle)置於Tyrode溶液中待實驗使用。
(2).實驗溶液：實驗主要於37℃下HEPES 之Tyrode溶液(以100﹪O2飽和)，或含bicaronate之Tyrode溶液 (以5﹪CO2/95﹪O2飽和）中進行。
(3).顯微螢光記錄儀（microspectrofluorimetry）：
利用顯微螢光技術，以氫離子敏感之螢光染劑BCECF ( 10μM )，分別透過不同之激發光波長激發（440 ﹠490 nm），於505 nm發散波長處接收螢光強度比值R （440 /490），比對校正曲線，以表示pHi濃度變化情形。
實驗結果：(1).在HEPES溶液條件下，Cl- - free及給與DBDS可以明顯抑制主動排鹼機轉。此主動排鹼機轉為Cl--dependent，可能為CHE (68%)及AE (26%)。
(2).給與quinidine ( 3μM ~ 100μM )對NHE的活性有劑量依賴性（dose-dependently）的抑制現象，但大劑量時( 300μM )抑制作用無增加。
(3).給與amiodarone ( 30 μM ~ 300μM)會呈劑量依賴性（dose-dependently）的增加NHE的活性。
(4).給與DeHE ( 0.3μM ~ 30μM )會呈劑量依賴性（dose-dependently）的增加NHE的活性。
結論 本研究首次在人類心臟細胞中報導有類似CHE及AE之主動排鹼運輸蛋白（transporters）。另外，也發現常用抗心律不整用藥quinidine、amiodarone及研發中之中藥有效成份DeHE，均對NHE之活性有調控之作用。其中DeHE及 classⅢ之amiodarone作用相似，會增加NHE之活性，但相反的，quinidine會抑制NHE之活性。

Introduction
Intracellular pH (pHi) regulation is particularly important for cardiac cells, because changes in pHi affect not only contraction but also rhythms. Our laboratory has demonstrated previously that Na+-H+ exchanger (NHE) and Na+-HCO3- symporter (NHS) are responsible for acid extrusion in the human myocardium. However, thus far, the carriers defending intracellular alkalosis have not been characterized in the human myocardium. Amiodarone and quinidine, typical antiarrhythmic drugs, have been wildly used in clinics to protect against life-threaten cardiovascular collapse. Dehydroevodiamine alkaloid (DeHE), an active ingredient of a Chinese herbal medicine Wu-Chu-Yu (Evodiae frutus), has been claimed to be a potential novel antiarrhythmic drug with the similar effects of type III (K+-channel blocker) antiarrhythmic drugs. However, effects of these antiarrhythmic drugs on pHi regulation have not been examined yet.
Aims
The aims of our present study were, using human atrial myocardium, to
(1)investigate the transporters for acid loading.(2)explore the effects of antiarrhythmic drugs (quinidine、amiodarone and DeHE) on pHi.
Materials and Methods
Human atrial myocardiums were obtained from the hearts undergoing corrective cardiac surgery for the treatment of congenital and acquired heart diseases. The change of pHi was detected by the technique of microspectrofluorimetry with a proton sensitive, dual excitation emission fluoroprobe, BCECF.
Results
In HEPES-buffered Tyrode solution, the addition of DBDS (0.3 mM), a specific inhibitor of Cl-/OH- exchanger (CHE), and removal of [Cl-]o could inhibit 68 + 8 ﹪（n=7）and 94 + 2 % （n=4）, respectively, of pHi recovery slope (measured at pHi=7.43+0.03;n=7 and pHi=7.59+0.01;n=4) following Na-acetate induced intracellular alkalosis. Quinidine（30 mM~100 mM）inhibited the activity of NHE, dose dependently. However, the inhibitory effect on NHE activity was not increased in the higher concentration（300 mM）of quinidine. Amiodarone（3 ~ 300 mM） and DeHE（0.3 ~ 30 μM）both increased NHE activity, dose dependently.
Conclusions
Our results demonstrated for the first time that, in the human atrium, (i) CHE and AE are likely the main acid loaders responsible for the acid loading mechanism; (ii) quinidine, amiodarone and DeHE all can regulate NHE activity. Amiodarone and DeHE show similar effect by increasing NHE activity, while quinidine inhibit NHE activity.

目錄
頁次
目錄--------------------------------------------------------------------------------------I
圖目錄-----------------------------------------------------------------------------------IV
中文摘要--------------------------------------------------------------------------------VI
英文摘要--------------------------------------------------------------------------------IX
第一章 序論---------------------------------------------------------------------------1
第一節 細胞內pH值恆定的重要--------------------------------------------1
壹、 主動或被動運輸細胞內氫離子-----------------------------------2
貳、 pHi regulator的證實-------------------------------------------------3
參、 排酸蛋白Na+/H+ exchanger（NHE）----------------------------4
肆、 排酸蛋白Na+/ HCO3- exchanger（NHS）-----------------------6
伍、 排鹼蛋白Cl-/HCO3- exchanger（AE）---------------------------6
陸、 排鹼蛋白Cl-/OH- exchanger（CHE）----------------------------7
第二節 pHi恆定對心臟功能的影響-------------------------------------------8
壹、 pH值與心肌收縮力--------------------------------------------------8
貳、 缺血後再灌流與pHi--------------------------------------------------8
參、 心肌缺血後再灌流與NHE-----------------------------------------10
第三節 心律不整與心律不整藥物分類--------------------------------------11
壹、 心律不整形成的機制-----------------------------------------------12
貳、 心律不整的分類-----------------------------------------------------13
參、 心律不整藥物分類--------------------------------------------------13
第四節 quinidine的藥理介紹-------------------------------------------------14
壹、 quinidine的簡介與藥理作用--------------------------------------15
貳、 quinidine藥物動力學-----------------------------------------------15
第五節 amiodarone的藥理介紹----------------------------------------------16
壹、 amiodarone的簡介與藥理作用-----------------------------------16
貳、 amiodarone的藥物動力學-----------------------------------------17
第六節 去氫吳茱萸鹼的藥理介紹-------------------------------------------18
第二章 材料與方法------------------------------------------------------------------20
第一節 藥品與溶液-------------------------------------------------------------20
第二節 實驗標本----------------------------------------------------------------21
第三節 螢光比值與細胞技術與細胞內pH值的關係--------------------22
壹、 利用螢光染劑測量pHi的原理------------------------------------22
貳、 載入螢光染劑BCECF----------------------------------------------23
參、 pHi校正----------------------------------------------------------------23
第四節 實驗裝置-----------------------------------------------------------------25
壹、 實驗裝置之架置------------------------------------------------------25
貳、 儀器原理與設備----------------------------------------------------25
第五節NH4Cl pre-pulse 技術------------------------------------------------26
第六節 Sodium acetate pre-pulse技術--------------------------------------27
第七節 統計方法---------------------------------------------------------------28
第三章 實驗結果---------------------------------------------------------------------29
第一節 人類心房細胞上排鹼蛋白之證實----------------------------------30
第二節 抗心律不整藥物quinidine對人類心臟排鹼蛋白之影響------32
第三節 抗心律不整藥物amiodarone對人類心臟排鹼蛋白之影響---33
第四節 抗心律不整藥物DeHE對人類心臟排鹼蛋白之影響----------34
第四章 討論---------------------------------------------------------------------------36
第一節 人類心臟組織的排鹼機轉-------------------------------------------36
第二節 NHE抑制劑在臨床上的可能運用---------------------------------37
第三節 quinidine對人類心臟組織排酸蛋白NHE的影響--------------39
第四節 amiodarone對人類心臟組織排酸蛋白NHE的影響-----------40
第五節 DeHE對人類心臟組織排酸蛋白NHE的影響------------------41
第五章 結論---------------------------------------------------------------------------43
第六章 參考文獻---------------------------------------------------------------------69
圖目錄
圖1 天竺鼠心室細胞調控蛋白-----------------------------------------------45
圖2 quinidine化學結構式-----------------------------------------------------46
圖3 amiodarone化學結構式--------------------------------------------------47
圖4 DeHE化學結構式---------------------------------------------------------48
圖5 螢光染劑BCECF激發光譜圖------------------------------------------49
圖6 載入螢光染劑BCECF之原理------------------------------------------50
圖7 pH值原位校正法----------------------------------------------------------51
圖8 螢光強度比值與pHi之關係圖------------------------------------------52
圖9 顯微螢光測定法-----------------------------------------------------------53
圖10 NH4Cl pre-pulse誘導細胞內酸化的原理-----------------------------54
圖11 sodium acetate pre-pulse誘導細胞內鹼化的原理--------------------55
圖12 在HEPES緩衝溶液中，細胞外無Cl-環境對人類心房細胞
排鹼能力的影響----------------------------------------------------------57
圖13 細胞外無Cl-環境對人類心房細胞排鹼能力的影響之統計圖---58
圖14 在HEPES緩衝溶液中，DBDS對人類心房細胞
排鹼能力的影響----------------------------------------------------------59
圖15 DBDS對人類心房細胞排鹼能力的影響之統計圖-----------------60
圖16 在HEPES緩衝溶液中，不同劑量quinidine對人類心房細胞NHE的影響----------------------------------------------------------------------61
圖17 不同劑量quinidine對人類心房細胞NHE的影響之統計圖-----62
圖18 高劑量quinidine對人類心房細胞NHE的影響--------------------63
圖19 在HEPES緩衝溶液中，不同劑量amiodarone對人類心房細胞NHE的影響---------------------------------------------------------------64
圖20 不同劑量amiodarone對人類心房細胞NHE的影響之統計圖--65
圖21 在HEPES緩衝溶液中，不同劑量DeHE對人類心房細胞pH值之影響----------------------------------------------------------------------66
圖22 在HEPES緩衝溶液中，不同劑量DeHE對人類心房細胞NHE的影響----------------------------------------------------------------------67
圖23 不同劑量DeHE對人類心房細胞NHE的影響之統計圖---------68
表一 抗心律不整藥依作用機轉分類----------------------------------------55
表二 抗心律不整藥依臨床症狀用藥分類----------------------------------56

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