IK1減量調節而產生自發性動作電位的電生理特性探討：電腦模型的模擬研究

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林益弘(Yi-Hong Lin) 查詢紙本館藏

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生命科學系

論文名稱

IK1減量調節而產生自發性動作電位的電生理特性探討：電腦模型的模擬研究
(Electrophysiological Characterization of IK1-downregulation-mediated Automaticity: A Model Study)

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摘要(中)

IK1是由向內整流型鉀離子通道(The potassium inward rectifier channel)所產生的電流，在第三階段的再極化效應(repolarization)與最主要的作用在第四階段再極化效應，將正在興奮階段的膜電位拉回靜止膜電位(resting membrane potential RMP)並且維持，直到下次的去極化效應(depolarization)產生。將IK1減量調節可能會產生的自發性動作電位，這個是安德森氏症(Andersen-Tawil Syndrome ATS)病人會產生心律不整的其中一個機制，那IK1減量調節驅使動作電位(IK1-downregulation-mediated Automaticity IDRMA)也可以拿來當做生物性起博器的研發機制。我們將使用的是哺乳類天竺鼠(guinea pig)心室心肌細胞的電腦模型來當我們模擬的材料。安德森氏症病患發生心律不整時，常常是由運動或是有情緒壓力時所引起的，我們將使用模擬模型(LRd2007模型)來探討β-腎上腺素刺激作用(Beta -Adrenergic Stimulation BAS)的機制。模擬β-腎上腺素刺激作用與低鉀離子效應(Hypokalemia)在IK1減量調節下的產生動做電位反應，觀察膜上面的離子通道的變化以及鈣離子的濃度變化，發現主要是因為INCX所產生的ITi，而使膜電位上升，誘導產生的CICR(Calcium-induced calcium release)為其主要的機制。也測試了許多離子通道阻斷劑，發現IDRMA可以抵抗InsCa，IK1 還有 IUP的離子通道阻斷劑的效應，另外發現到使用INaK的離子通道阻斷劑會使得IDRMA發生的時間點提早，若是ATS病人不小心服用了含有INaK的離子通道阻斷劑的心血管用藥或是誤食了毛地黃，都會產生嚴重的心律不整，生命將會有危險。

摘要(英)

The inward rectifier (IK1) channel is responsible for shaping the phase 3 repolarization and maintaining the phase 4 membrane potential. Downregulation of IK1 may occur spontaneous action potentials referred to as automaticity. This is one of the arrhythmogenic mechanisms of Andersen-Tawil syndrome and also is one of principles applied to generate biological pacemakers. We use a guinea pig ventricular myocyte model, we sought to elctrophysiologically characterize the IK1-downregulation mediated automaticity (IDRMA). Since VTs in ATS are often triggered exacerbated by exertion and emotional distress, we use a simulation model(LRd2007 model) to define the role of beta-adrenergic stimulation in the genesis of VTs. Specifically, we observe responses of IDRMA to simulated hypokalemia, and pharmacological interventions. On detailed analysis of membrane ionic events and submembrane Ca2+ cycling, thereby responsible for the onset of IDRMA. IDRMA was resistant to InsCa，IK1 and IUP blockers, and was only partially responding to combination of INCX and InsCa blockade, IUP and ICa,L blockade. Of note, IDRMA could be aggravated by INaK blockade.

關鍵字(中)

★ 電腦模擬
★ 安德森氏症
★ β-腎上腺素刺激

關鍵字(英)

★ beta-adrenergic stimulation (BAS)
★ computational simulation
★ Andersen-Tawil syndrome(ATS)

論文目次

目錄
前言…………………………………………………………………………-1-
實驗材料及方法…………………………………………………………-4-
實驗結果…………………………………………………………………-6-
IK1減量調節的程度測試…………………………………………………-6-
影響IDRMA的離子通道及鈣離子循環…………………………………-7-
IK1減量調節、β-腎上腺素刺激與低鉀離子效應的模擬實驗………………-9-
IK1減量調節之下剔除及獨立β-腎上腺素刺激的因子實驗……………-10-
藥理模擬－離子通道阻斷劑的測試………….…………………………-11-
討論……………………………………………………………………-13-
圖表…………………………………………………………………………-16-
參考文獻………………………………………………………………-29-
附錄………………………………………………………………………-33-

參考文獻

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指導教授

宋瑞珍(Ruey J. Sung)

審核日期

2010-7-15

推文