臺灣博碩士論文加值系統

前言:
心房纖維顫動 (atrial fibrillation, AF) 乃心律不整中最常見的症狀，主要是心房出現快速混亂的電位活性，導致心房節律異常快速，造成嚴重的心臟功能不良以及腦中風。肺靜脈 (pulmonary veins, PVs)是造成陣發性心房纖維顫動以及引發異位性心房心律不整之重要病灶所在。異常鈣離子調節造成電活動異常，增加細胞內鈣離子瞬變和肌漿網鈣儲存，提高肺靜脈心律失常活動。心房利鈉肽 (atrial natriuretic peptide, ANP)，由心房心肌細胞產生的 28 個胺基酸，屬於 polypeptide 類賀爾蒙，具利尿鈉、利尿、血管舒張、抑制腎素- 醛固酮系統和交感神經活動，心房利鈉肽是透過第二信息 cyclic guanosine monophosphate (cGMP) 和 Cyclic adenosine monophosphate (cAMP) 抑制心肌細胞鈣離子超載。先前研究證實，心房利鈉肽可以預防術後心房顫動的發生，但心房利鈉肽對於肺靜脈心肌組織的電性活性機轉及細胞內鈣離子濃度恆定影響尚不清楚。
目的:
本研究的目的是在探討心房利鈉肽對於肺靜脈心肌組織，其電性活性及細胞內鈣離子恆定的作用，以及異丙腎上腺素 (isoproterenol, ISO) 誘發心律不整的影響。
材料方法:
將 16 週大、2.5~ 3 公斤紐西蘭大白兔之肺靜脈心肌組織及肺靜脈心肌細胞分離後，使用傳統電生理及 fluo-3/AM 鈣離子螢光染色法紀錄給予心房利鈉肽前後，其電生理特性和細胞內鈣離子濃度變化。
結果:
1. 與控制組 1.9±0.2 Hz 相比，心房利鈉肽 (1, 10, 100 nM) 濃度增加可以減少肺靜脈心肌組織的自動節律性 1.8±0.2、1.6±0.2、1.5±0.2 Hz。心房利鈉肽 (100 nM) 顯著降低肺靜脈心肌組織自動節律性 (N=8, P<0.05)。
2. 心房利鈉肽 (100 nM) 減少異丙腎上腺素對於肺靜脈心肌組織所誘導之不規律電性活性的產生，並減少異丙腎上腺素所誘導較快速的自動節律性。
3. 給予 AP811 (ANP clearance receptor抑制劑, NPR- C 抑制劑, 100 nM) 顯著降低異丙腎上腺素對於肺靜脈心肌組織所誘導的不規律電性活性及自動節律性，隨之加入心房利鈉肽 (100 nM) 無明顯改變不規律電性活性的發生，自動節律性也無顯著改變。
4. 給予 H89 (PKA 抑制劑, 10 M) 顯著降低V誘導肺靜脈心肌組織產生的不規律電性活性及自動節律性，隨之加入心房利鈉肽 (100 nM) 無明顯改變不規律電性活性的發生，自動節律性也無顯著改變。
5. 給予 KT5823 (PKG 抑制劑, 1 M) 顯著異丙腎上腺素誘導肺靜脈心肌組織產生的不規律電性活性及自動節律性，隨之加入心房利鈉肽 (100 nM) 持續減少不規律電性活性的發生，自動節律性無顯著改變。
6. 給予 wortmannin (PI3K 抑制劑, 100 nM) 減少異丙腎上腺素誘導肺靜脈心肌組織所產生的不規律電性活性及自動節律性，隨之加入心房利鈉肽 (100 nM) 持續減少不規律電性活性的發生，自動節律性無顯著改變。
7. 控制組與心房利鈉肽 (100 nM) 別相比，心房利鈉肽 (100 nM) 組別 Ca2+ transient 表現明顯較低。
結論:
心房利鈉肽能有效降低肺靜脈心肌組織自動節律性及細胞內鈣離子濃度變化。在異丙腎上腺素誘導肺靜脈心肌組織心律不整的情況下，心房利鈉肽會透過與 NPR- A 及 NPR- C 結合，抑制或活化 second messenger cAMP/ cGMP 訊號，進而活化 PKG 及抑制 PKA、PI3K 活性，降低肺靜脈心肌組織自動節律性頻率，減少異丙腎上腺素所誘導的肺靜脈心肌組織心律不整的發生。

Introduction:
Atrial fibrillation (AF) is the most common form of arrhythmia. AF is an irregular and often rapid heart beat that increase risk of stroke and cardiac dysfunction. Pulmonary veins (PVs) are an important source where atrial ectopic beats are generate to initiate AF. Abnormal calcium (Ca2+) plays a role in triggering irregular electrical activity of PV cardiomyocytes. Atrial natriuretic peptide (ANP) exhibits natriuretic, diuretic and vasorelaxant activity. The natriuretic peptide receptor (NPR) preferentially binds ANP and regulates secondary messenger cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) inhibit Ca2+ overload.
Purposes:
It is not clear if ANP modulates the electrophysiological characteristics and Ca2+ homeostasis in the PV.
Materials and Methods:
Conventional microelectrodes, and the fluo-3 fluorimetric ratio technique were used to record electrophysiological characteristics and intracellular Ca2+ in isolated rabbit PV preparations or in single isolated PV cardiomyocytes before and after ANP treatment.
Results:
Compared with control (1.9±0.2Hz), ANP (1, 10, and 100 nM) concentration dependently decreased spontaneous electrical activity (1.8±0.2, 1.6±0.2, 1.5±0.2 Hz) in PV preparations. ANP (100 nM) decreased spontaneous electrical activity (N=8, P<0.05). Compared with control, ANP (100 nM) decreased intracellular Ca2+ transient in PV cardiomyocytes (2.0  0.2 F/F0 vs 1.4  0.1, P< 0.001). Isoproterenol (ISO, 1 μM)- treated PV preparations (N=13) increased the incidence of burst firing (*) and spontaneous electrical activity (1.8  0.2 Hz vs 3.5  0.1 Hz, P< 0.001) than PV preparations than those without ISO (1 μM) treatment, and ANP can ameliorate the effect of ISO (1 μM) on PV preparations. AP811 (100 nM, NPR-C inhibitor) decreased ISO-induced PV spontaneous electrical activity and burst firing, but ANP did not further suppress ISO-induced PV spontaneous electrical activity and burst firing. H89 (1μM, PKA inhibitor) decreased ISO-induced PV spontaneous electrical activity and burst firing, which became more decrease combined with ANP treatment. KT5823 (1 μM, PKG inhibitor) or wortmannin (100 nM, PI3K inhibitor) did not change ISO-induced PV spontaneous electrical activity and burst firing, and ANP have no effects on ISO-induced PV burst firing and spontaneous electrical activity in the presence of KT5823 or wortmannin.
Conclusion:
ANP directly regulates PV electrophysiological characteristics and calcium homeostasis, and attenuates ISO-induced arrhythmogenesis through NPR- C- PKA, NPR- A- PKG and PI3K signal pathway.

目錄 I
表目錄 IV
圖目錄 V
中文摘要 VII
英文摘要 X
第一章、 緒論 1
第一節、心房纖維顫動 (Atrial fibrillation) 1
第二節、心房利鈉肽 (Atrial natriuretic peptide) 2
第三節、左心房- 肺靜脈 (Left atrium- pulmonary vein, LA-PV) 6
第四節、心律不整的機轉 7
第五節、細胞內鈣離子恆定 9
第二章、研究目的 12
第三章、材料與方法 13
第一節、實驗動物 13
第二節、實驗藥物及溶液的配置 13
第三節、左心房–肺靜脈動作電位和收縮張力紀錄 14
第四節、肺靜脈鈣離子螢光染色技術 16
第五節、左心房與肺靜脈心肌組織給予心房利鈉肽 (ANP) 之電生理實驗設計 17
第六節、鈣離子螢光 19
第七節、實驗數據分析 19
第四章、實驗結果 20
第一節、心房利鈉肽對肺靜脈組心肌組織與左心房心肌組織電生理特性的影響 20
第二節、心房利鈉肽對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性的影響 21
第三節、心房利鈉肽及 AP811 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性的影響 22
第四節、心房利鈉肽及 H89 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性的影響 23
第五節、心房利鈉肽及 KT5823 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性的影響 24
第六節、心房利鈉肽及 Wortmannin 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性的影響 25
第七節、心房利鈉肽對肺靜脈心肌細胞之細胞內鈣離子濃度的影響 27
第五章、討論 45
第一節、心房利鈉肽對肺靜脈組心肌組織與左心房心肌組織電生理特性之探討 45
第二節、心房利鈉肽對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性之探討 46
第三節、心房利鈉肽及 AP811 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性之探討 47
第四節、心房利鈉肽及 H89 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性之探討 48
第五節、心房利鈉肽及 KT5823 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性之探討 49
第六節、心房利鈉肽及 Wortmannin 對異丙腎上腺素所誘導肺靜脈心肌組織心律不整之電生理特性之探討 50
第七節、心房利鈉肽對肺靜脈心肌細胞之細胞內鈣離子濃度之探討 51
第六章、結論 53
第七章、參考文獻 54

表目錄
表 1、當異丙腎上腺素 (1 mM) 誘導出肺靜脈心肌組織爆發性放電的情況下，再給予心房利鈉肽 (100 nM) 對其頻率變化情形。 42
表 2、當異丙腎上腺素 (1 mM) 誘導出肺靜脈心肌組織爆發性放電的情況下，單獨給予 KT5823 (1 mM) 和同時給予 KT5823 (1 mM) 及心房利鈉肽 (100 nM) 對其頻率變化情形。 43
表 3、當異丙腎上腺素 (1 mM) 誘導出肺靜脈心肌組織爆發性放電的情況下，單獨給予 Wortmannin (100 nM) 和同時給予 Wortmannin (100 nM) 及心房利鈉肽 (100 nM) 對其頻率變化情形。 44

圖目錄
圖 1、心房利鈉肽對自動節律性肺靜脈心肌組織電生理特性的影響。 28
圖 2、心房利鈉肽對左心房心肌組織電生理特性的影響。 29
圖 3、心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 30
圖 4、心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 31
圖 5、單獨給予 AP811 和同時給予 AP811 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。單獨給予心房利鈉肽和同時給予 AP811 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 32
圖 6、單獨給予 AP811 和同時給予 AP811 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 34
圖 7、單獨給予 H89 和同時給予 H89 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 35
圖 8、單獨給予 H89 和同時給予 H89 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 36
圖 9、單獨給予 KT5823 和同時給予 KT5823 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 37
圖 10、單獨給予 KT5823 和同時給予 KT5823 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 38
圖 11、單獨給予 Wortmannin 和同時給予 Wortmannin 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 39
圖 12、單獨給予 Wortmannin 和同時給予 Wortmannin 及心房利鈉肽對異丙腎上腺素 (ISO) 所誘導肺靜脈心肌組織心律不整之電生理特性的影響。 40
圖 13、控制組及給予心房利鈉肽 (100 nM) 肺靜脈心肌細胞鈣離子濃度變化。 41
圖 14、心房利鈉肽作用路徑。 53

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