臺灣博碩士論文加值系統

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 mM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。

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 mM 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 mM. 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.

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

Reference
Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 2002;17:43-51.
Ashford ML, Boden PR, Treherne JM. Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflugers Arch 1990;415:479-483.
Baker JE, Contney SJ, Gross GJ, Bosnjak ZJ. KATP channel activation in a rabbit model of chronic myocardial hypoxia. J Mol Cell Cardiol 1997;29:845-848.
Biliczki P, Virag L, Iost N, Papp JG, Varro A. Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve. Br J Pharmacol 2002;137:361-368.
Carlsson L, Abrahamsson C, Andersson B, Duker G, Schiller-Linhardt G. Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations. Cardiovasc Res 1993;27:2186-2193.
Davie C, Pierre-Valentin J, Pollard C, Standen N, Mitcheson J, Alexander P, Thong B. Comparative pharmacology of guinea pig cardiac myocytes and cloned hERG (IKr) channel. J Cardiovasc Electrophysiol 2004;15:1302-1309.
Faivre JF, Findlay I. Action potential duration and activation of ATP-sensitive potassium current in isolated guinea-pig ventricular myocytes. Biochim Biophys Acta 1990;1029:167-172.
Ferrero JM Jr, Saiz J, Ferrero JM, Thakor NV. Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K+ current. Circ Res 1996;79:208-221.
Findlay I. Inhibition of ATP-sensitive K+ channels in cardiac muscle by the sulphonylurea drug glibenclamide. J Pharmacol Exp Ther 1992;261:540-545.
Findlay, I. The ATP sensitive potassium channel of cardiac muscle and action potential shortening during metabolic stress. Cardiovasc Res 1994;28:760-761.
Fosset M, De Weille JR, Green RD, Schmid-Antomarchi H, Lazdunski M. Antidiabetic sulfonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels. J Biol Chem 1988;263:7933-7936.
Gasser RN, Vaughan-Jones RD. Mechanism of potassium efflux and action potential shortening during ischaemia in isolated mammalian cardiac muscle. J Physiol 1990;431:713-741.
Gibb WJ, Wagner MB, Lesh MD. Effects of simulated potassium blockade on the dynamics of triggered cardiac activity. J Theor Biol 1994;168:245-257.
Gima K, Rudy Y. Ionic current basis for the electrocardiographic waveforms: A model study. Circ Res 2002;90:889-896.
Grant AO, Strauss LJ, Wallace AG, Strauss HG. The influence of pH on the electrophysiological effects of lidocaine in guinea pig ventricular myocardium. Circ Res 1980;47:542-550.
Hamada E, Takikawa R, Ito H, Iguchi M, Terano A, Sugimoto T, Kurachi Y. Glibenclamide specifi-cally blocks ATP-sensitive K+ channel current in atrial myocytes of guinea pig heart. Jpn J Pharmacol 1990;54:473-477.
Han J, So I, Kim EY, Earm YE. ATP-sensitive potassium channels are modulated by intracellular lactate in rabbit ventricular myocytes. Pflugers Arch 1993;435:546-548.
Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Faranz M, Malik M, Moss A, Shah R. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000;21:1216-1231.
Holahan MA, Stranieri MT, Stabilito II, Lynch JJ Jr. Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury. J Cardiovasc Pharmacol 1992;19:892-898.
Hua F, Gilmour RF Jr. Contribution of IKr to rate-dependent action potential dynamics in canine endocardium. Circ Res 2004;94:810-819.
Irisawa H, Sato R. Intra- and extracellular actions of proton on the calcium current of isolated guinea pig ventricular cells. Circ Res 1986;59: 348-355.
Jurkiewicz BS, Wang J, Ferminin B, Sanguinetti MC, Salata JJ. Mechanism of action potential prolongation by RP 58866 and its active enantiomer, terikalant. Block of the rapidly activating delayed rectifier K+ current, IKr. Circulation 1996;94:2938-2946.
Kagiyama Y, Hill JL, Gettes LS. Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in guinea pig ventricular muscle. Circ Res 1982;51;614-623
Kakei M, Noma A, Shibasaki T. Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol (Lond) 1985;363:441-462.
Kléber AG. Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig hearts. Circ Res 1994;52:442-450.
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., Kangawa, K. Ghrelin is a growth-hormonereleasing acylatedpeptid e from stomach. Nature 1999;402:656-660.
Lederer WJ, Nichols CG, Smith GL. The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition. J Physiol (Lond) 1989;413:329-349.
Li G-R, Feng J, Yue L, Carrier M, Nattel S. Evidence for two components of delayed rectifier K+current in human ventricular myocytes. Circ Res 1996;78:689-696.
Li RA, Leppo M, Miki T, Seino S, Marban E. Molecular basis of electrocardiographic ST-segment elevation. Circ Res 2000;87:837-839.
Light PE, Cordeiro JM, French RJ. Identification and properties of ATP-sensitive potassium channels in myocytes from rabbit Purkinje fibres. Cardiovasc Res 1999;44:356-369.
Liu D-W, Antzelevitch C.haracteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, mid-myocardial, and endocardial myocytes. Circ Res 1995;76:351-365.
Luo CH, Rudy Y. A dynamic model of the cardiac ventrticular action potential. I. Simulation of ionic currents and concentration changes. Circ Res 1994;74:1071-1096.
Matsuoka S, Sarai N, Kuratomi S, Ono K, Noma A. Role of individual ionic current systems in ventricular cells hypothesized by a model study. Jpn J Physiol 2003;53:105-123.
Neto FR, Junior OM, Olivera GB. Antiarrhythmic and electrophysiologcal effects of the novel KATP channel opener, rilmakalim, in rabbit cardiac cells. Gen Pharmacol 1997;29:201-205.
Nichols CG, Ripoll C, Lederer WJ. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ Res 1991;68:280-287.
Nichols CG., Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol 1991 261;(6 Part 2):H1675-1686.
Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983;305:47-148.
Obreztchikova MN, Sosunov EA, Plotnikov A, Anyukhovsky EP, Gainullin RZ, Danilo P Jr, Yeom Z-H, Robinson RB, Rosen MR. Developmental changes in IKr and IKs contribute to age-related expression of dofetilide effects on repolarization and proarrhythmia. Cardiovasc Res 2003;59:339-350.
Priebe L, Beuckelmann DJ. Simulation study of cellular electric properties in heart failure. Circ Res 1998;82:1206-1223.
Quayle JM., Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 199777:1165-1232.
Rocchetti M, Besana A, Gurrola GB, Possani LD, Zaza A. Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential. J Physiol 2001;534:721-732.
Rodríguez B, Ferrero JM Jr, Trénor B. Mechanistic investigation of extracellular K+ accumulation during acute myocardial ischemia: a simulation study. Am J Physiol Heart Circ Physiol 2002;283:H490-H500.
Saito T, Sato T, Miki T, Seino S, Nakaya H. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am J Physiol Heart Circ Physiol 2005;288:H352-357.
Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+current. Differential sensitivity to block by class III anti-arrhythmic agents. J Gen Physiol 1990;96:195-215.
Seino S, Miki T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol 2003;81:133-176.
Shang YP, Xie XD, Wang XX, Chen JZ, Zhu JH, Tao QM, Zheng LR. A novel splice mutation of HERG in a Chinese family with long QT syndrome. J Zhejiang Univ SCI 2005;6:626-630
Shaw RM, Rudy Y. Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration. Cardiovasc Res 1997;35:256-272.
Shaw RM, Rudy Y. Electrophysiological changes of ventricular tissue under ischemic conditions: a simulation study. Comp Cardiol 1994;16:641-644.
Shigematsu S, Arita M. Anoxia-induced activation of ATP-sensitive K+ channels in guinea pig ventricular cells and its modulation by glycosis. Cardiovasc Res 1997;35:273-282.
Shimizu W, Kurita T, Matsuo K, Suyama K, Aihara N, Kamakura S, Towbin JA, Shimomura K. Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome. Circulation 1998;97:1581-1588.
Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol 1996;7:503-511.
Skinner RB, Jr., Kunze DL. Changes in extracellular potassium activity in response to decreased pH in rabbit atrial muscle. Circ Res 1976;39:678-683.
Snyders DJ. Structure and function of cardiac potassium channels. Cardiovasc Res 1999;42:377-390.
Studenik CR, Zhou Z, January CT. Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome. Br J Pharmacol 2001;132:85-92.
Tamargo J, Caballero R, Gόmez R. Valenzuela C, Delpόn E, Pharmacology of cardiac potassium channels. Cardiovasc Res 2004;62:9-33.
Tan HL, Hou CJ, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;122:701-714.
Van Opstal JM, Leunissen JD, Wellens HJ, Vos MA. Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias. Eur J Pharmacol 2001;412:67-76.
Varró A, Baláti B, Iost N, Takács J, Virág L, Lathrop DA, Csaba L, Tálosi L, Papp JG. The role of the delayed rectifier component of IKs in dog ventricular muscle and Purkinje fibre repolarization. J Physiol 2000;523:67-81.
Varró A, Biliczki P, Iost N, Virág L, Hala O, Kovacs P, Matyus P, Papp JG. Theoretical possibilities for the development of novel antiarrhythmic drugs. Curr Med Chem 2004;11:1-11.
Viswanathan PC, Shaw RM, Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 1999;99:2466-2474.
Wang Z, Fermini B, Nattel S. Rapid and slow components of delayed rectifier current in human atrial myocytes. Cardiovasc Res 1994;28:1540-1546.
Weiss JN, Venkatesh N, Lamp ST. ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol 1992;447:649-673.
West PD, Bursill JA, Wyse KR, Martin DK. Campbell TJ, Effect of dofetilide and d-sotalol on the ATP-sensitive potassium channel of rabbit ventricular myocytes. J Cardiovasc Pharmacol Ther 1996;1:307-312.
Wilde AAM, Janse MJ. Electrophysiological effects of ATP sensitive potassium channel modulation: implications for arrhythmogenesis. Cardiovasc Res 1994;28:16-24.
Wit AL, Janse MJ. The ventricular arrhythmias of ischemia and infarction: electrophysiological mechanisms. New York: Futura Publishing Company, 1992:648.
Yamada M, Isomoto S, Matsumoto S, Kondo C, Shindo T, Horio Y, Kurachi Y. Sulphonylurea receptor 2B andKir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J Physiol 1997;499:715-720.
Yan GX, Kléber AG. Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circ Res 1992;71:460-470.
Yang Z, Shi G, Li C, Wang H, Liu K, Liu Y. Electrophysiologic effects of nicorandil on the guinea pig long LQT1 syndrome model. J Cardiovasc Electrophysiol 2004;15:815-820.
Yatani A, Brown AM, Akaike N. Effect of extracellular pH on sodium current in isolated, single rat ventricular cells. J Membr Biol 1984;78:163-168.
Zeng J, Laurita KR, Rosenbaum DS, Rudy Y. Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea-pig type: theoretical formulation and their role in repolarization. Circ Res 1995;77:140-152.
Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent G. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations. Characteristic T-U wave patterns predict the KCNJ2 genotype. Circulation 2005;111:2720-2726.