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系統識別號 U0026-0812200911571770
論文名稱(中文) 在心臟組織缺血與非缺血下活化ATP敏感性鉀離子電流與抑制快速活化鉀離子電流交互作用的臨床意義之模擬研究
論文名稱(英文) Clinical implications of interactions between IK(ATP) activation and IKr blockade during non-ischemic and ischemic conditions: a simulation study
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 94
學期 2
出版年 95
研究生(中文) 張漢東
研究生(英文) Han-Dong Chang
學號 s3693110
學位類別 碩士
語文別 英文
論文頁數 72頁
口試委員 指導教授-吳勝男
召集委員-潘偉豐
口試委員-羅錦興
中文關鍵字 心律不整  離子通道  模擬模型  心臟病  缺血 
英文關鍵字 Arrhythmia  Simulation model  Ischemia  Heart disease.  Ion channels 
學科別分類
中文摘要 ATP敏感性鉀離子通道活化劑 (例如: nicorandil ),常被用來使用在缺血性心臟病的病人的身上,另外快速活化鉀離子通道抑制劑(例如E-4031, d-sotalol, dofetilide, and sematilide)常被用在預防心室心律不整。
ATP敏感性鉀離子通道活化劑和快速活化鉀離子通道抑制劑兩種藥劑,都有抗心律不整和導致前心律不整的特性。於是在臨床上這兩種藥的交互作用是非常令人感興趣的。這次的研究中,我們使用Luo-Rudy的模型來模擬ATP敏感性鉀離子通道活化劑和快速活化鉀離子通道抑制劑兩種藥劑的效果,在單獨和合併以及缺血的情況之下,對於心臟動作電位的影響。
我們的結果顯示,當被快速活化鉀離子通道抑制50%的時候,動作電位的長度會從176微秒被延長到385微秒;然而當ATP敏感性鉀離子通道被活化50%的時候動作電位的長度會從385微秒縮短到124微秒。
另外在缺血的環境之下,不同的ATP細胞內濃度分別為300,100,30 M得情況之下時,動作電位的長度分別減少 11%,42%,72%。另外模擬結果顯示在缺血的情況下,ATP敏感性鉀離子通道活化劑和快速活化鉀離子通道抑制劑兩種藥劑的效果都會被減弱很多。總結來說,ATP敏感性鉀離子通道活化劑可以有效的縮短動作電位的長度,來抵消快速活化鉀離子通道抑制劑造成的心律不整現象,然而在缺血的情況之下,兩種藥物對動作電位幾乎不影響。





英文摘要 In patients with ischemic heart disease, openers of ATP-sensitive K+ current (IK(ATP)) (e.g., nicorandil) are increasingly used for angina and blockers of the rapidly activating K+ current (IKr) (e.g., E-4031, d-sotalol, dofetilide, and sematilide) are often prescribed for ventricular arrhythmias. Both IK(ATP) openers and IKr blockers possess antiarrhythmic and proarrhythmic properties. Potential interactions between these two classes of drugs may occur. In this study, we used dynamic Luo-Rudy simulation model to study the effects of IK(ATP) activation and IKr blockade, alone and in combination, on action potential duration (APD) of ventricular myocardium during control and under ischemic conditions. Our result showed that IKr blockade by 50% prolonged APD90 from 176 to 385 ms; however, subsequent IK(ATP) activation by 50% reduced the duration from 385 to 124 ms. Ischemic conditions created by varying concentrations of intracellular ATP at 300, 100 and 30 M progressively decreased APD90 by 11, 42 and 72%, respectively. The half-maximal concentration for intracellular ATP to shorten APD90 and to block IK(ATP) was calculated to be 87.5 M. Both IK(ATP) activation and IKr blockade did not exert any influence on ischemia. In conclusions, IK(ATP) activation is very potent in shortening ADD90 and may thereby diminish antiarrhythmic while suppress proarrhythmic effects of IKr blockade. Myocardial ischemia induces progressive shortening of APD90 in parallel with reduced ATP concentrations. However, profibrillatory propensity induced by myocardial ischemia would not be affected by either IK(ATP) activation or IKr blockade.




論文目次 Table of Contents
中文摘要………………………………………………………..............9
Abstract…………………………………………………………...........10
Introduction…………………………………………………………….....11
Methods………………………………………………………………........14
Cardiac ventricular cell model …………………………………………14
Ischemic cardiac ventricular cell model …………………………….15
Results…………………………………………………………………......17
Simulated action potential and rapidly delayed rectifier K+ current (IKr) based on the LRd model ……………………………………………………………17
Simulated action potential and ATP-sensitive K+ current (IK(ATP)) based on the LRd model…………………………………………………………………....17
Effect of IK(ATP) activation on early afterdepolarizations (EADs) induced by IKr blockade…………………………………………………………………18
Effect of IKr blockade on APD in simulated cell model compromised by ischemic insults……………………………………………………………….. .....19
Effect of IKr blockade on APD shortened by reduced intracellular ATP …20
Effect of IKr blockade on APD in simulated cell model compromised by ischemic insults………………………………………………..……………… .....20
Pseudo-ECG in simulated myocardial ischemia with or without inhibition of IKr……………………………………………………………………………….21
Discussion……………………………………………………………….......22
References………………………………………………………….…........25
Figure Legends………………………………………………………….......36
Appendix……………………………………………………………….........43
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