臺灣博碩士論文加值系統

心房顫動是最常見的持續性心律不整，且會增加中風、心衰竭和死亡的風險。心房顫動的危險因子包括鈣離子過載和氧化壓力等。研究顯示兒茶素（表沒食子兒茶素-3-沒食子酸酯，EGCG）具有抗氧化作用，且有益於保護心血管健康。然而，EGCG保護心血管健康的作用機轉及如何調節心臟的電生理特性並不清楚。本研究使用玻璃微電極、全細胞膜電位箝定和Fluo-3熒光計比率技術，來研究及記錄在兔子左心房組織或心肌細胞給予兒茶素EGCG前後動作電位、離子電流和細胞內鈣離子的變化。研究兒茶素EGCG（0.01,0.1,1和10μM）等4種濃度分別和縮短動作電位作用時間有正相關性，分別降低APD20 13±8％，25±5％，31±6％和37±5％，APD50降低9±8％，22± 6％，32±7％和40±4％，APD90為2±12％，9±8％，24±10％和34±5％。另外，兒茶素EGCG（0.1μM）會降低晚期鈉離子電流（INa-Late），L型鈣離子電流(ICa-L)和鈉-鈣離子交換電流(NCX)，但不會改變左心房心肌細胞中的鈉電流(INa)。兒茶素EGCG（0.1μM）也會減少左心房心肌細胞中的細胞內鈣離子和肌漿網鈣離子含量。兒茶素EGCG可抑制利用異丙腎上腺素（ISO，1μM）誘發的心房顫動，給予兒茶素EGCG（0.1μM）治療前和同時給予KT5823（1μM，PKG抑制劑）或KN93（1μM，CaM激酶抑制劑）也都抑制了ISO（1μM）誘發的心房顫動的發生率，但單獨使用H89（10μM，PKA抑制劑）或PKI抑制劑都不會抑制ISO（1μM）誘發的心房顫動的發生率。然而，在H89或PKI抑制劑存在下，兒茶素EGCG（0.1μM）仍然抑制了ISO（1μM）誘發的心房顫動的發生率。
結論，兒茶素EGCG可能透過直接調節左心房電生理特性和鈣離子調控，並通過抑制鈣調蛋白或cGMP依賴性蛋白激酶抑制異丙腎上腺素誘導的心房心律不整。

Atrial fibrillation (AF) is the commonest sustained arrhythmia, and gives rise to the risk of stroke, heart failure, and mortality. Many factors are considered to participate in the pathogenesis of AF, including calcium (Ca2+) overload and oxidative stress. Epigallocatechin-3-gallate (EGCG) has a well-know clinical effectiveness, such as an antioxidative potential to medical care, and has been shown to be beneficial in promoting cardiovascular health. However, it is still unclear whether EGCG directly modulates the electrophysiological characteristics and Ca2+ homeostasis of the left atrium (LA). Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorometric ratio technique were applied to record action potentials (APs), ionic currents and intracellular Ca2+ within isolated rabbit LA preparations or isolated single LA myocytes before and after the administration of EGCG. EGCG (0.01, 0.1, 1, and 10 μM) which concentration-dependence decreased the APD20 by 13±8%, 25±5%, 31±6%, and 37±5%, APD50 by 9±8%, 22±6%, 32±7%, and 40±4%, and APD90 by 2±12%, 9±8%, 24±10%, and 34±5% in LA cardiomyocytes. EGCG (0.1 μM) decreased the late sodium (Na+) current, L-type Ca2+ current, and nickel-sensitive Na+-Ca2+ exchanger current, but did not change the Na+ current in LA cardiomyocytes. EGCG (0.1 μM) decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in LA cardiomyocytes. Furthermore, EGCG decreased isoproterenol (ISO, 1 μM)-induced burst firing. KT5823 (1 μM, a PKG inhibitor) or KN93 (1 µM, a CaM kinase inhibitor) decreased the incidences of ISO (1 μM)-induced LA burst firing, which became lower with EGCG (0.1 μM) treatment. H89 (10 µM, a PKA inhibitor) did not suppressed the incidence of ISO (1 μM)-induced LA burst firing. However, EGCG (0.1 μM) decreased the incidences of ISO (1 μM)-induced LA burst firing in the presence of H89.
In conclusion, EGCG directly regulates LA electrophysiological characteristics and Ca2+ homeostasis, and suppresses isoproterenol-induced atrial arrhythmogenesis through inhibiting Ca2+/calmodulin or cGMP-dependent protein kinases.

第一章 前言-------------------------------------------------------------------------------------1
1.1 兒茶素 (Epigallocatechin-3-gallate)---------------------------------------------1
1.2 心律不整(arrhythmia)--------------------------------------------------------------3
1.3 心房顫動(atrial fibrillation) -------------------------------------------------------6
1.4 心臟肥大(cardiac hypertrophy)---------------------------------------------------7
1.5 左心房(left atrium, LA)------------------------------------------------------------8
1.6 心肌細胞電生理學之簡介--------------------------------------------------------9
1.7 動作電位與離子電流之簡介----------------------------------------------------10
1.8 活性氧分子(Reactive oxygen species, ROS)------------ ---------------------13
1.9 研究目的---------------------------------------------------------------------------15
第二章 材料與方法-------------------------------------------------------------------------16
2.1 實驗動物---------------------------------------------------------------------------16
2.2 實驗藥物及溶液的配製---------------------------------------------------------17
2.3 玻璃微電極與細胞膜電位箝定實驗-------------------------------------------17
2.4傳統電生理實驗-------------------------------------------------------------------19
2.5 鈣離子測定------------------------------------------------------------------------20
2.6 Langendorff 離體心臟實驗------------------------------------------------------22
2.7 電生理及藥理學的研究---------------------------------------------------------22
2.8 實驗數據與統計------------------------------------------------------------------21
第三章 結果------------------------------------------------------------------------------------24
3.1兒茶素EGCG對左心房組織電生理特性的影響---------------------------24
3.2兒茶素EGCG對左心房心肌細胞膜離子通道的影響-------------------- 26
3.3兒茶素EGCG對左心房鈣離子的調控----------------------------------------30
3.4兒茶素EGCG對異丙腎上腺素誘發的左心房心律不整的影響----------32
3.5兒茶素與KN93、KN92、 KT5823、H89、PKI等抑制劑對異丙腎上腺素誘發左心房顫動的影響------------------------------------------------------------34
第四章 討論------------------------------------------------------------------------------------41
4.1 兒茶素EGCG對左心房組織電生理特性的影響----------------------------41
4.2 兒茶素EGCG對左心房細胞電生理、離子流特性的影響----------------41
4.3 兒茶素EGCG對左心房作用機轉研究----------------------------------------44
4.4 研究限制----------------------------------------------------------------------------45
第五章 結論------------------------------------------------------------------------------------46
參考文獻----------------------------------------------------------------------------------------47

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