1.Ca～（2+）转运机制—Na～+/Ca～（2+）交换对狗心室肌细胞复极的影响 2.动作电位参数作为区分狗心室肌心内膜、心外膜和心肌中层M细胞的可行性研究
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摘要
研究背景和目的：人类及哺乳类动物心脏的复极期极为重要，因为它不仅调节兴奋和传导，而且还调节收缩活动。复极的异常往往导致心律失常和/或泵功能异常。可能参与复极的离子流有瞬间外向钾离子流(I_(to))，钙离子流(I_(Ca))，快钾离子流(I_(kr))，慢钾离子流(I_(ks))，内向整流离子流(I_kl))及钠—钙交换电流(I_(NCX))等。目前，国内外已有很多有关I_(to)、I_(Ca)、I_(kl)、I_(kr)、I_(ks)和心室肌复极关系的研究报道。不同部位的心室肌细胞所含离子流的种类和数量不同，因而表现为不同的电活动特性以及对药物和病理学状态的不同反应(电异质性)，所致的透壁性心室肌复极离散(transmural dispersion of repolarization，TDR)是致心律失常性单向阻滞和折返的重要机制。近年来的研究发现同一心肌细胞的动作电位时程(action potential duration，APD)的变异很可能为心律失常的另一机制。推测细胞膜上的钠-钙转运蛋白(Na~+/Ca~(2+)exchange，NCX)可能是影响APD变异的重要因素之一。目前，国外研究病理状态下的NCX电生理特性的报道较多。Studer 1994年首先报道在人类心衰时NCX的mRNA表达上调，在心肌肥厚和心衰的动物模型以及人类心衰终末期NCX的表达和/或活性增强。提示NCX活性改变在心肌肥厚和心衰中的重要性在于其对收缩功能的影响和心电紊乱事件的引发，NCX的非对称性离子转运(3个Na~+交换1个Ca~(2+))实际上起生电效应，必然影响复极过程。NCX的顺向模式是在细胞松弛时将钙离子转运出细胞外。生理状态下的NCX逆向转运模式在复极中的意义还不甚明确。目前NCX的离子转运模式失调是否为引发心律失
常的另一重要机制的研究，在国内外是一个前沿课题。本课题研究的
目的在于探讨生理状态下NCX双向模式的离子转换对复极的影响，
以及在转换失调时是否成为潜在的触发心律失常的机制。
方祛：单个心室肌细胞试验。动物来源20只成年雄性杂种狗心
脏。用Langandorff冠状动脉左前降支（LAD）灌注法，灌注无钙
液和低钙胶原酶液分离单个左心室肌细胞。被灌注的组织经切碎，过
滤，冲铣后保存在 17℃，含抗菌素的生理液中待用 门～3 6h）。应
用细胞膜钳片技术，在钳电流的模式下记录动作电位归ction
potential，AP卜测定在生理状态下细胞的电生理特征，AP以及收缩
的参数。并用统计学方法评价所测量的参数是否将心内膜，心外膜及
M细胞有效地区分开。用光感边缘探测器测定细胞的短缩状况以代
表细胞的收缩活动。在钳电压的模式下，I讹x应用钙装载程序（Cay
一loading protocol）测定。将电压从“0mV钳至＋60my水平，持续
600msec以充分激活NCX的逆向模式。进行钙的装载。再将膜电位
钳回＊0inV，并持续600iiis盯。此时记录到的电流即INCX。继而将
膜电位钳至omV，并持续500msec再将电压钳至＊0mV。膜电位为
oniV时记录到的电流为IC。L。
结果：固定频率刺激APD的变化范围和频率改变时APD的变
化范围均在一个相对固定的膜电位范围内 卜40～＋10mV）。用
10mM EGTA缓冲细胞内游离钙后，APD的变异系数（coefficient
varianility，CV）明显减刁（2．3土0．8～1．3土0．3，pwto，of）。而废除
SR功能及应用钙通道阻滞剂nifedipine并不改变APD的变异程度
（P＞0．05）。说明 NCX模式转换的随机性造成细胞内游离钙的彼
动，而细胞内游离钙的波动是APD变异的关键。另外我们在不同细
胞观察到了因刺频率减慢（0．6HZ～1．OHZ）造成复极和细胞松弛的
不匹配，从而导致后收缩（After七ontraction，A－CON）的出现 以
及 APD的延长（278fsmsec～320igmsec MeanfSD，n—5，50 APs，
Pwto．05）。其原因考虑为NCX逆向活性的加强引起的SR内钙的蓄
积及钙的自发释放。因此又测定了在强化NCX逆向活性的条件下
（用 40mM Li”替换 40mM Na“以减低细胞外 Na‘浓度），穹隆膜
— —一
电位显著降低＊．8士0．3—q 石士1卫mV，Prto刀5），而APD显著
延长＊30土 13～368土 14thSCC，P＜0．05）。结果还显示 10 11M
ryanodine和 3 u M thapsigargin废除 SR功能时，细胞收缩幅度明显
减J（2．1士0．2～二．2士0．l，P＜0．05）。10nM ISO虽可以增力收
缩幅度（＊＊土0．2～3．8土0．4，P＜0．01），却不能增加收缩上升的
速度（542士234～3 54士27mVlmsec，Pwto．05）。说明SR作为细
胞内的贮钙机制，在其ryano山ne受体激活后，钙大量快速的释放对
收缩的重要作用。
IsoproterenolO）模拟神经体液因素作用，本试验以其为工具
研究对以上NCX参与的钙转运机制的影响以及诱发心律失常的机
制。小剂量ISO＊）的作用下，细胞平均需要60个AP，l刀Hi刺
激约1分钟的时间达到新的稳定状态，表现为收缩幅度的增加。但在
较大剂量的uO作用下（10、20、50nM）细胞因出现不规律的延迟
／早期后除极（delayed／early after－depolerization，DAD／EAD）及
A－CON均未达到新的平衡。随ISO剂量的增大，EAD，DAD及A－
CO
Background and aims: Naturally occurring temporal variability of action potential duration (APD) in isolated myocytes has been noted. Most of the studies have been focusing on analyzes of the differences in ionic channels and currents among the epicardial-, mid-myocardial-(M) and endocardial myocytes, and the rate-dependent (adaptation) characteristics of APD. We have found that the change in APD during a change in frequency of stimulation mostly reflects a change in rate of repolarization at distinct membrane potential levels.
We assumed that in the myocytes, there is balancing mechanism, which is constantly adjusting the various ionic currents accommodating to the changing conditions. This intrinsic ability of adaptation is important and may offer some of the consequences of the transmural heterogeneity in adaptation of APD. This adaptive behaviors maybe equally important in maintaining the normal electrophysiological properties and in induction of arrhythmia in a case of error in normal adaptation. Though most studies of Na+/Ca2+ exchange (NCX) has been emphasized on its reverse activaty during pathyological condition. Our hypothesis is that reverse activaty of NCX also plays an important role in adjusting the repolarization of AP during a physiological condition. A mismatch between action potential (AP) repolarization and relaxation of the contraction can be caused by intracellular Ca2+ transport abnormalities. Ca2+ influx via reverse activation of NCX can load the sarcoplasmic recticulum (SR), which has arrhythmogenic effect.
Methods: We studied the single myocytes from the heart of adult mongrel dogs. During the cell separation, Ca2+ -free Tyrode, low Ca2+ (60#,M) BS containing collagenase was perfused through LAD by Langandorff system. The tissue perfused by the LAD was then minced into a suspension, filtered , washed and resuspended 5 times in BS. The myocytes were stored in a minimum essential medium with Hank's salt at 17癈. Penicillin (100,000 u/L) inhibited bacterial growth in the storage medium. We determinded AP in current clamp mode, we verified the origin of each myocyte by examining the characteristics of the APs under baseline conditions. By this method we managed to separate the three types of myocytes very effectively. Myocyte contraction was imaged by a video camera, shortening of unloaded myocytes was detected by a video edge
motion detector, using changes in light intensity at the edges of themyocyte.INcx was recorded in voltage clamp mode and activated by Ca2+loading protocol..Re8uItst From 60 consecutive recorded APs at a constant 1.0 Hzstimulation under steady state conditions we found there is avariance in the repolarization between l0mV and -40mV. We alsofound the variance in the APD during the rate adaptation range ofrepolarization. Fluctuation in the transient may contribute to theAPD variability. To test this hypothesis we block the transient byintracellular dialysis with l0 mM EGTA(n=l9), this caused asignificant reduction in the coeffcient variability (CV=SD/meanAPD%) from 2.3t0.8 to l .3t0.3 p <0.0l. During a rate change ofthe stimulation from 0.6Hz to 1.0Hz. The AP duration increasedfrom 278l8msec to 320f9msec (MeanlSD, n=5, 50 APs, P<0.05),contraction is accompanied by an after-contraction(A-CON). There1axation of contraction precedes the repolarization of the AP. Weassumed that the enhancemcnt of repolarization and the productionof after-contraction can be possibly induced by reverse mode ofNCX. Reducing [Na+l. by substitution of 40mM Na+ with Li+ favorsNCX actiyating the reverse mode, which significantly decreased thedome of the AP from 4.8 i 0.3 to -- 10.6 i l .2mV(P < 0.05) andincreased the APD from 330 I l3 to 368 f l4msec(P < 0.05). Whenthe SR function was abolished by 10 u M ryanodine and 3 ll Mthapsigargin, contraction was significantly decreased (from 2.l l0.2 tol .2 l 0. l, P r 0.05) o 10nM isopretorenol (ISO) can onlyincrease the amplitude of the contraction (from 2.l I 0.2 .to 3 .8 i0.4, P wt 0.0l), but the rate of rise decreased (542 I 234 to 354
常的另一重要机制的研究，在国内外是一个前沿课题。本课题研究的
目的在于探讨生理状态下NCX双向模式的离子转换对复极的影响，
以及在转换失调时是否成为潜在的触发心律失常的机制。
方祛：单个心室肌细胞试验。动物来源20只成年雄性杂种狗心
脏。用Langandorff冠状动脉左前降支（LAD）灌注法，灌注无钙
液和低钙胶原酶液分离单个左心室肌细胞。被灌注的组织经切碎，过
滤，冲铣后保存在 17℃，含抗菌素的生理液中待用 门～3 6h）。应
用细胞膜钳片技术，在钳电流的模式下记录动作电位归ction
potential，AP卜测定在生理状态下细胞的电生理特征，AP以及收缩
的参数。并用统计学方法评价所测量的参数是否将心内膜，心外膜及
M细胞有效地区分开。用光感边缘探测器测定细胞的短缩状况以代
表细胞的收缩活动。在钳电压的模式下，I讹x应用钙装载程序（Cay
一loading protocol）测定。将电压从“0mV钳至＋60my水平，持续
600msec以充分激活NCX的逆向模式。进行钙的装载。再将膜电位
钳回＊0inV，并持续600iiis盯。此时记录到的电流即INCX。继而将
膜电位钳至omV，并持续500msec再将电压钳至＊0mV。膜电位为
oniV时记录到的电流为IC。L。
结果：固定频率刺激APD的变化范围和频率改变时APD的变
化范围均在一个相对固定的膜电位范围内 卜40～＋10mV）。用
10mM EGTA缓冲细胞内游离钙后，APD的变异系数（coefficient
varianility，CV）明显减刁（2．3土0．8～1．3土0．3，pwto，of）。而废除
SR功能及应用钙通道阻滞剂nifedipine并不改变APD的变异程度
（P＞0．05）。说明 NCX模式转换的随机性造成细胞内游离钙的彼
动，而细胞内游离钙的波动是APD变异的关键。另外我们在不同细
胞观察到了因刺频率减慢（0．6HZ～1．OHZ）造成复极和细胞松弛的
不匹配，从而导致后收缩（After七ontraction，A－CON）的出现 以
及 APD的延长（278fsmsec～320igmsec MeanfSD，n—5，50 APs，
Pwto．05）。其原因考虑为NCX逆向活性的加强引起的SR内钙的蓄
积及钙的自发释放。因此又测定了在强化NCX逆向活性的条件下
（用 40mM Li”替换 40mM Na“以减低细胞外 Na‘浓度），穹隆膜
— —一
电位显著降低＊．8士0．3—q 石士1卫mV，Prto刀5），而APD显著
延长＊30土 13～368土 14thSCC，P＜0．05）。结果还显示 10 11M
ryanodine和 3 u M thapsigargin废除 SR功能时，细胞收缩幅度明显
减J（2．1士0．2～二．2士0．l，P＜0．05）。10nM ISO虽可以增力收
缩幅度（＊＊土0．2～3．8土0．4，P＜0．01），却不能增加收缩上升的
速度（542士234～3 54士27mVlmsec，Pwto．05）。说明SR作为细
胞内的贮钙机制，在其ryano山ne受体激活后，钙大量快速的释放对
收缩的重要作用。
IsoproterenolO）模拟神经体液因素作用，本试验以其为工具
研究对以上NCX参与的钙转运机制的影响以及诱发心律失常的机
制。小剂量ISO＊）的作用下，细胞平均需要60个AP，l刀Hi刺
激约1分钟的时间达到新的稳定状态，表现为收缩幅度的增加。但在
较大剂量的uO作用下（10、20、50nM）细胞因出现不规律的延迟
／早期后除极（delayed／early after－depolerization，DAD／EAD）及
A－CON均未达到新的平衡。随ISO剂量的增大，EAD，DAD及A－
CO
Background and aims: Naturally occurring temporal variability of action potential duration (APD) in isolated myocytes has been noted. Most of the studies have been focusing on analyzes of the differences in ionic channels and currents among the epicardial-, mid-myocardial-(M) and endocardial myocytes, and the rate-dependent (adaptation) characteristics of APD. We have found that the change in APD during a change in frequency of stimulation mostly reflects a change in rate of repolarization at distinct membrane potential levels.
We assumed that in the myocytes, there is balancing mechanism, which is constantly adjusting the various ionic currents accommodating to the changing conditions. This intrinsic ability of adaptation is important and may offer some of the consequences of the transmural heterogeneity in adaptation of APD. This adaptive behaviors maybe equally important in maintaining the normal electrophysiological properties and in induction of arrhythmia in a case of error in normal adaptation. Though most studies of Na+/Ca2+ exchange (NCX) has been emphasized on its reverse activaty during pathyological condition. Our hypothesis is that reverse activaty of NCX also plays an important role in adjusting the repolarization of AP during a physiological condition. A mismatch between action potential (AP) repolarization and relaxation of the contraction can be caused by intracellular Ca2+ transport abnormalities. Ca2+ influx via reverse activation of NCX can load the sarcoplasmic recticulum (SR), which has arrhythmogenic effect.
Methods: We studied the single myocytes from the heart of adult mongrel dogs. During the cell separation, Ca2+ -free Tyrode, low Ca2+ (60#,M) BS containing collagenase was perfused through LAD by Langandorff system. The tissue perfused by the LAD was then minced into a suspension, filtered , washed and resuspended 5 times in BS. The myocytes were stored in a minimum essential medium with Hank's salt at 17癈. Penicillin (100,000 u/L) inhibited bacterial growth in the storage medium. We determinded AP in current clamp mode, we verified the origin of each myocyte by examining the characteristics of the APs under baseline conditions. By this method we managed to separate the three types of myocytes very effectively. Myocyte contraction was imaged by a video camera, shortening of unloaded myocytes was detected by a video edge
motion detector, using changes in light intensity at the edges of themyocyte.INcx was recorded in voltage clamp mode and activated by Ca2+loading protocol..Re8uItst From 60 consecutive recorded APs at a constant 1.0 Hzstimulation under steady state conditions we found there is avariance in the repolarization between l0mV and -40mV. We alsofound the variance in the APD during the rate adaptation range ofrepolarization. Fluctuation in the transient may contribute to theAPD variability. To test this hypothesis we block the transient byintracellular dialysis with l0 mM EGTA(n=l9), this caused asignificant reduction in the coeffcient variability (CV=SD/meanAPD%) from 2.3t0.8 to l .3t0.3 p <0.0l. During a rate change ofthe stimulation from 0.6Hz to 1.0Hz. The AP duration increasedfrom 278l8msec to 320f9msec (MeanlSD, n=5, 50 APs, P<0.05),contraction is accompanied by an after-contraction(A-CON). There1axation of contraction precedes the repolarization of the AP. Weassumed that the enhancemcnt of repolarization and the productionof after-contraction can be possibly induced by reverse mode ofNCX. Reducing [Na+l. by substitution of 40mM Na+ with Li+ favorsNCX actiyating the reverse mode, which significantly decreased thedome of the AP from 4.8 i 0.3 to -- 10.6 i l .2mV(P < 0.05) andincreased the APD from 330 I l3 to 368 f l4msec(P < 0.05). Whenthe SR function was abolished by 10 u M ryanodine and 3 ll Mthapsigargin, contraction was significantly decreased (from 2.l l0.2 tol .2 l 0. l, P r 0.05) o 10nM isopretorenol (ISO) can onlyincrease the amplitude of the contraction (from 2.l I 0.2 .to 3 .8 i0.4, P wt 0.0l), but the rate of rise decreased (542 I 234 to 354
引文
[1] January CT, Riddle JM, Salata JJ: A model for early afterdepolarizations: Induction with the Ca~(2+) channel agonist Bay K 8644. Circ Res, 1988, 62:563-571
[2] El-Sherif N, Craelius W, Boutijdir M et al. Early afterdepolarizations and arrhythmogenesis. J Cardiovasc Electrophysiol. 1990, 1:145-160
[3] Szabo B, Sweidan R, Rajagopalan CV et al. Role of Na~+/ Ca~(2+) exchange current in Cs~+-induced early afterdepolarizaton in Purkinje fiber. J Cardiovasc Electrophysiol. 1994, 5:933-944
[4] Szabo B, Rajagopalan CV, Lazzara R. The role of Na~+/ Ca~(2+) exchange in generation of early afterdpolarization in cardiac action potentials. FASEB J, 1992, 6:A1164
[5] Studer R, Reinecke H,Bilger J ey al. Gene expression of the Na~+/ Ca~(2+) exchange in end stage human heart failure. Circ Res.1994, 75:443-453
[6] Bum RC, Francis B, Guy S. Cytosolic Ca~(2+) triggers early afterdepolarization and Torsade de Pointes in rabbit heart with type 2 long QT syndrome. Journal of Physiology. 2002, 543(2):615-631
[7] Karin RS, Paul GA, Volder MA et al. Altered NCX activity in cardiac hypertrophy and heart failure: a new target for therapy. Carc Res. 2002, 53:782-805
[8] Elizabeth AW, Jane FA, Sharon NH et al. Reperfusion-induced Ins(1,4,5) P3 generation and arrhythmogenesis require activation of the Na~+/ Ca~(2+) exchange. J Moll Cell. Cardiol. 2001, 33:1961-1869
[9] Antzelevitch C. The M cell. Invited Editorial Comment. J Cardiovasc, Pharmacol Ther. 1997,2:73-76.
[10] Antzelevitch C, S Sicouri SH, Litovsky A et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cell. Circ Res. 1991,69: 1427-1449.
[11] Anyukhovsky EP, Sosunov EA, Cainullin RZ et al. The controversial M cell. J Cardiovasc, Electrophysiol. 1999, 10: 244-260
[12] Liu DW and Antzelevitch C. Characteristics of the delayed rectifier current (I_(kr) and I_(ks)) in canine ventricular epicardial, midmyocardial and endocardial myocytes: a weaker I_(ks) contributes to the longer action potential of the M cell. Circ Res. 1995:76:351-365
[13] Francis LB and Stuart MC. Dispersion of ventricular repolarization and refractory period. Carc Res, 2001, 50:10-23
[14] Kiyosue T and Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ, Res. 1989, 64:389-397
[15] Li CZ, Wang XD, Wang HW et al. Four types of late Na channel current in isolated ventricular myocytes with reference to their contribution to the lastingness of action potential plateau. Acta Physiol. Sinica. 1997,49:241-248
[16] Lesh MD, Pring M and Spear JF, Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study. Circ. Res. 1989.65: 1426-1440
[17] Massimiliano Z, Andrew EP, Yang L et al. Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling. Am J Physiol. Heart Circ Physiol. 2000, 278:677-687
[18] Blaustein MP and Lederer WJ. Sodium/calcium exchange: it's physiological implications. PhysiolRev. 1999, 79(3):763-854
[19] Conway SJ, Koushik SV. Cardiac sodium-calcium exchanger: a double-edged sword. Cardiovasc Res 2001, 51(2): 194-7
[20] Antzelevitch C. Ion channels and ventricular arrhythmogenesis. Cellular and ionic mechanisms underlying the Brugada syndrome. Curr Opin Cardiol 1999, 12:274-279
[21] Richard S,Leclercq F, Lemarie S et al. current in compensated hypertrophy and the heart failure. Cardiovasc Res. 1998, 37:300-311
[22] Goldhaber JI. Metabolism in normal and ischemic myocardium in the Myocardium. Langer GA(ed) 2nd. San Diego, CA, Academic Press. 1997,325-393
[23] Clapham DE, Shrier A and DeHaan RL. Junctional resistance and action potential delay between embryonic heart cell aggregates. J Gen Physiol. 1980, 75:633-654
[24] Konta TK, Ikeda M, Yamaki K et al, Significant of discordant ST alternans in ventricular fibrillation. Circulation. 1990,82: 2185-2189
[25] Smith JM, Sato N, Tanaka H et al. Electrical alternans and cardiac electrical instability. Circulation. 1988, 77:110-121
[26] Kay GN, Plumb VJ, Arciniegas JG et al. Torsades de pointes: The long-short initiating sequence and other clinical feature. Observations in 32 patients. J Am Coll Cardiol. 1990, 2:806-817
[27] Denker S, Lehman M, Mahmua R et al. Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol. 1984, 53:505-515
[28] El-Sherif N, Gough WB, Restivo M. Reentrant ventricular arrhythmias in the late myocardial infarction period. Mechanisms by which a short-long-short cardiac sequence facilitates the induction of reentry. Circulation. 1991, 83:268-278
[29] Wier WG. [Ca~(2+)]_ⅰ Transient during excitation-contaction coupling of mammalian heart, in Fozzard HA, Haber E, Jennings RB Katz AM, Morgan HE (eds): The Heart and Cardiovascular System, Ed 2. New York, Raven Press. 1991, 1223-1248
[30] Hilgemann DW. "Best estimates" of physiological Na/Ca exchange function: calcium conservation and the cardiac electrical cycle, in Zipes DP, Jalife J (eds): Cardiac Electrophysilogy. Saunders Co. 1990, 51-61
[31] Barcenas-Ruiz L, Wier WG. Voltage dependence of intracellular [Ca~(2+)]_ⅰ transient in guinea pig ventricular myocytes. Circ Res 1987, 61:148-154
[32] Fabiato A. Stimulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic recticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985, 85:291-320
[33] Szabo B, Kovacs T, Lazzara R. Cesium increases intracellular uptake of calcium and increases force development in cardiac
ventricular muscle during the evolution of early afterdepolarization. J Am Coll Cardiol. 1990, 15:77-79
[34] Belardinelli L, Isenberg G: Actions of adenosine and isoproterenol on isolate mammalian ventricular myocytes. Circ Res.1983,53:287-297
[35] Rosenberg RL, Hess P, Tsien RW. Cardiac calcium channels in planar lipid bilayers. L-type channel and calciumOpermeable channels open at negative membrane potentials. J Gen Physiol. 1988, 92:27-54
[36] Patterson E, Szabo B, Scherlag BJ et al. Realy and delayed afterdepolarizations associated with cesium chloride-induced arrhymias in the dog. J Cardiovasc Pharrnacol. 1990,15:323-331
[37] Bers DM. Species differences and the role of sodium-calcium exchange in cardiac muscle relaxation, in Blaustein MP, Dipolo R, Reeves JP (eds). Sodium calcium exchange. New York, Annals of New York Academy of Science, 1991,12:375-385
[38] Song Y, Belardinelli L. ATP promotes development of afterdepolarizations and triggered activity in cardiac myocytes. Am J Physiol. 1994, 267:2005-2011
[39] Perchenet L, Hinde AK, Patel KCR et al. Stimulation of NCX by the Beta-adrenergic/protein kinase . a pathway in guinea-pig ventricular myocytes at 37oC, Pflugers Arch. 2000, 439:822-828
[40] Eigel BN, Hadley RW. Antisense inhibition of NCX during anoxia/reoxygenation in ventricular myocytes. Am J Physiol. 2001, 281:2184-2190
[41] Kass RS, Tsien RW. Control of action potential duration by calcium ions in cardiac Purkinje fibers. J Gen Physiol. 1976, 67:599-617
[42] McC. Brooks C, Hoffman BF, Suckling EE, Orias O. The effects of heart rate, action of autonomic nerves and chemical mediators on cardiac excitability, in McC.Brooks C, Hoffman BF, Suckling EE, Orias O (eds). Excitability of the Heart. New York, Grune & Strstton, 1995, 21:221-222
[43] Bogdanov KY, Vinogadova TM, Lakatta EG et al. Sinoatrial nodal cell ryanodine receptor and NCX . Molecular partners in pacemaker regulation. Circ Res. 2001, 88:1254-1258
[44] Kohmoto O, Levi AJ, Brige JHB. Relation between reverse NCX and Sarcoplasmic reticulum calcium release in guinea pig ventricular cells. Circ Res. 1994,74:50-554
[45] Sipido KR, Voiders, PG, DeGroot SH et al. Enhanced Calcium release and NCX activity in hypertrophied canine ventricular myocytes. Potential link between contractile adaptation and arrhythmogenesis. Circulation, 2000, 102:2137-2144
[46] Blaustein MP, Lederer WJ. Sodium/calcium exchange: its physiological implications. Physiol Rev. 1999, 79:763-854
[47] Kimura J, Miyamae A, Noma. Identification of sodium calcium exchange current in single ventricular cells of guinea-pig. J physiol. 1987,384:199-222
[48] Janvier NC, Boyett MR. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res. 1996, 32:69-84
[49] Rigg L, Terrar DA. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sinoatrial node. Exp Physiol, 1996, 81:877-880
[50] Shigekawa M, Iwamoto T. Cardiac Na-Ca exchange: molecular and pharmacological aspects. Circ Res. 201, 88:864-876
[51] Lipp P, Schwaller B, Niggli E. Specific inhibition of Na-Ca exchange function by anti-sense oligodeoxynucleotides. FEBS Lett. 1995, 364:198-202
[52] Spipido KR, Volder PG, Vos MA, Verdonck F. Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res. 2002 , 53(4):782-805. Review.
[53] Houser SR, Piacentino V Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000, 32(9):1595-607. Review.
[54] Kubota I, Tomoike H, Han X, Sakurai K. The Na~+-Ca~(2+) exchanger contributes to beta-adrenoceptor mediated positive inotropy in mouse heart. Japanese Heart Journal. 2002, 43(4): 399-407
[55] Segers M, Le role des potentials tardifs du Coeur. Mem Acad R Med Belg Series Ⅱ, 1941, (1), fascile 7. 1-30
[56] Bezier E. The initiation of impulses in cardiac muscle. Am J Physiol. 1943, 138:273-282
[57] Davis LD. Effect of changes in cycle lenth on diastolic depolarization produced by ouabain in canine Purkinje fibers. Circ Res. 1973, 32:206-214
[58] Rose MR. Gelband H, Hoffman BF. Correlation between effects of ouabain on the canine electrocardiogram and transmembrane potentials of isolated Purkinje fibers. Circulation. 1973, 47:65-72
[59] Cranefield P. Action potentials, afterpotentials and arrhythmias. Circ Res. 1977, 41:415-423
[60] Brachmann J, Scherlag BJ, Rosenshtraukh LV, Lazzara R. Bradycardia-dependent triggered activity: relevance to druginduced multiform ventricular tachycardia. Circulation. 1983, 68:846-856
[61] Volder PG, Kulscar A, Vos MA et al. Similarities between early and delayed afterdepolarizations induced by isoproterenol
in canine ventricular myocytes. Cardiovasc Res. 1997, 34: 348-359
[62] Janury CT, Riddle JM, Salata JJ. A model for early afterdepolarizations: Mechanism of induction and block: a role for L-type Ca~(2+) current. Circ Res. 1989, 64:977-990
[63] Zeng J, Rudy Y. Early afterdepolarization in cardiac myocytes: mechanism and rate dependence. Biophys J. 1995, 68:949-964
[64] Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of NCX current in Cs~+-induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol, 1994, 5:933-944
[65] Szabo B, Kovacs T, Lazzara R. Role of calcium loading in early afterdepolarizations generated by Cs~+ in canine and guinea pig Purkinje fibers. J Cardiovasc Electrophysiol. 1995, 6:796-812
[66] Shimizu W, Ohe T, Kurita T et al. Epinephrine-induced ventricular premature complete atriventricular block and torsade de pointes. Pacing Clin Electrophysiol. 1993, 126:33-38
[67] Sato T, Hata Y, Yamamoto M et al. Early afterdepolarization abolished by potassium channel opener in a patient with idiopathic long QT syndrome. J Cardiovasc Electrophysiol. 1995, 6:279-282
[68] Shimizu W, Kurita T, Matsuo K et al. Improvement of repolarization abnormalities by a K~+ channel opener in the LQTS form of congenital long-QT ayndrome. Circulation. 1998,97:1581-158
[69] Spitzer KW, Sato H, Tanaka L et al. Electrotonic modulation of electrical activity in rabbit strioventricular node myocytes. Am J Physiol. Heart Circ Physiol. 1997,273:767-776
[70] Babij PG, Askew B, Nieuwenhuijsen CM et al. Inhibition of cardiac delayed rectifier K~+ current by overexpression of the
long-QT syndrome HERG G628S mutation in transgenic mice. Circ Res. 1998, 83:668-678
[71] Sanguinetti MC, Jiang C, Curran ME et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the Ikr potassium channel. Cell. 1995, 81: 299-307
[72] Saiz J, Ferrero JM, Monserrat M et al. Influence of electrical coupling on early afterdepolarizations in ventricular myocytes. IEEE Trans. Biomed Eng. 1999, 46:138-147
[73] Wilders R and Jongsma HJ. Beating irregularity of single pacemaker cells isolated from the rabbit sinoatial node. Biophys J. 1993, 65:2601-2613
[74] Liu YL, Defelice J and Mazzanti M. Sodiom channels that remain open throughout the cardiac action potential plateau. Biophys J. 1992:63:645-662
[75] Kiyosue T and Arita M. Late sodium current and its contribu-tion to action potential configuration in guinea pig ventricular myocytes. Circ Res. 1989, 64:389-397
[76] Li CZ, Wang XD, Wang HW et al. Four types of late Na channel current in isolated ventricular myocytes with reference to their contribution to the lastingness of action potential plateau. Acta Physiol. Sinica. 1997, 49:241-248
[77] Huelsing DJ, Spitzer KW, Cordeiro JM et al. Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol. Heart Circ Physiol. 1998, 274:1163-1173
[78] Huelsing DJ, Spitzer KW, Cordeiro JM et al. Modulation of repolarization in rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol. Heart Circ Physiol. 1999, 276:572-581
[79] Liu DW, Gitant GA and Antzelevitch C. Ionic bases for electrophysiologieal distinctions among epicardial, midmyocardial and endocardial myocytes from the free wall of the canine left ventricle. Cite Res. 1993, 72:671-687
[80] You YD, Pelzer J and Pelzer S. Modulation of L-type calcium current by fast and slow calcium buffering in guinea pig ventricular cardiomyocytes. Biophys. 1997,72: 175-187
[81] Cheng MB, Cheng BH and Lederer WJ. Spatial non-uniformities in Ca during excitation-contraction coupling in cardiac myocytes.
[82] Cheng H, Lederer WJ and Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993, 262:740-744
[83] Lopez-Lopez J, Schackloek PS, Balke CW et al. Local stochastic release of Ca~(2+) in voltage clamped rat heart cells: visualization with confocal microscopy. J Physiol (Lond). 1994, 480:21-29
[84] Goldman Y, Morad M. Ionic membrane conductance during the time course of the cardiac action potential. J Physiol(Lond). 1997, 268:655-695
[85] Weidmann S. Effect of current flow on the membrane potential of cardiac muscle. J Physiol. (Lond), 1991, 115:227-236
[86] Wagner JA, Weisman HF, Snowman AM et al Alterations in calcium antagonist receptors and sodium-calcium exchange in cardiomyopathic hamster tissues. Circ Res. 1989, 65:205-214
[87] David DM, Pernollet MG, LeQuan SH et al. Active Na~+ and Ca~(2+) transport, Na~+ -Ca~(2+) exchange and intracellular Ca~(2+) and Na~+ content in young spontaneously hypertensive rats. J Cardiovase Phamacol. 1986, 8:130-135
[88] Nakanishi H, Makino N, Hata T et al. Sarcolemmal Ca~(2+) transport activities in cardiac hypertrophy caused by pressure overload. Am J Physiol, 1989, 257:349-356
[89] Brooks WW, Bing OH, Boluyt MO et al. Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. Hypertension. 2000, 35:1203-1209
[90] Andrawis NS, Kou TH, Giacomelli F et al. Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. J Mol Cell Cardiol.1988, 20:625-634
[91] Naqvi RU, Macleod KT, Effect of hypertrophy on mechanisms of relaxation in isolated cardiac myocytes from guinea pig. Am J Physiol. 1994, 267:1851-1861
[92] Heyliger CE, Takeo S, Dhalla NS. Alteration in sarcolemmal Na~+ -Ca~(2+) exchange
[93] McCall E, Ginsburg KS, Bassani RA et al. Ca flux contractility and excitation- contraction coupling in hpertrophic rat ventricular myocytes. Am J Physiol. 1998, 274:1346-1360
[94] Wang Z, Nolan B, Kutschke W, Hill JA. Na~+ -Ca~(2+) exchange remodeling in pressure-overload cardiac Hypertrophy. J Biol Chem. 2001, 276:177706-17711
[95] Vos MA, de Groot SH, Verduyn SC et al. Enhanced susceptibility for acquired torsade de points arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation. 1998, 98:1125-1135
[96] Sipido KR, Volder PGA, Groot SH et al. Enhanced Ca~(2+) release and Na~+ -Ca~(2+) exchange activity in hypertrophied canine ventricular myocytes: a potential link between contractile adaptation and arrhymogenesis. Circulation, 2000, 102:2137-2144
[97] Verdonck F, Voider PGA, Vos MA et al. Cardiac hypertrophy is associated with an increase in subsarcolemmal Na~+ .Biophys J. 2001, 80:589
[98] Volders PGA, Sipido KR, Vos MA et al Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation, 1998, 98:1136-1147
[99] Volders PGA, Sipido KR, Vos MA et al. Downregulation of delayed rectified K current in dogs with chronic complete atrioventricular block and acquired torsades de point, Circ Res, 1999, 84:562-570
[100] O'Rourke B, Kass DA, Tomaselli GF et al. Mechanisms of altered excitation-contraction coupling in canine tachycardiainduced heart failure. Experiment studies. Circ Res, 1999,84:562-570
[101] Yao A, Su Z, Nonaka A et al. Abnormal myocyte homeostasis in rabbits with pacing-induced heart failure. Am J Physiol. 1998, 87:690-698
[102] Tsuji Y, Opthof T, Kamiya K et al. Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreased in calcium and transient outward current in rabbit ventricle. Cardiovasc Res. 2000, 48:300-309
[103] Vermeulen JT, McGuire MA, Opthof T et al. Triggered activity and automaticity in ventricular traceculae of failing human and rabbit hearts. Cardiovasc Res. 1994, 28:1547-1554
[104] Pogwizd SM. Nonreentrant mechanisms underlying spontaneous ventricular srrhythmias in a model of nonischemic heart failure in rabbits. Circulation. 1995, 92:1034-1048
[105] Aygmunt AC, Goodrow RJ, Antzelevitch C. I_(NCX) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol. 2000, 278:1671-1678
[106] Matiello JA, Margulies KB, Jeevanandam V et al. Contribution of reverse mode sodiumpcalcium exchange to contractions in failing human left ventricular myocyte. Cardiovasc res. 1998, 37:424-431
[107] Gaughan JPm Furukawa S, Jeevanandam V et al. Sodium/calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. Am J Physiol. 1999, 277: 714-724
[108] Dipla K, Mattiello JA, Margulies KB et al. The sarcoplasmic recticulum and the Na~+ -Ca~(2+) exchange both contribute to the Ca~(2+) transient of failing human ventricular myocytes. Circ Res. 1999, 84:435-444
[109] Iwamoto T, Watano T, Shigekawa M. A novel isothiourea derivative selectively inhibits the reverse mode of Na~+ -Ca~(2+) exchange in cells expressing NCX1, J Biol Chem. 1996, 271:22391-22397
[110] Kimura J, Watano T, Shigekawa M et al. Direction-independent block of Na~+ -Ca~(2+) exchange bi-directional current by KBR7943 in guinea-pig cardiac myoeytes. Br J Pharmacol. 1999, 128:969-974
[111] Heerdt PM, Holmes JW, Cai B et al. Chronic unloading by left ventricular assit device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000, 102:2713-2791
[2] El-Sherif N, Craelius W, Boutijdir M et al. Early afterdepolarizations and arrhythmogenesis. J Cardiovasc Electrophysiol. 1990, 1:145-160
[3] Szabo B, Sweidan R, Rajagopalan CV et al. Role of Na~+/ Ca~(2+) exchange current in Cs~+-induced early afterdepolarizaton in Purkinje fiber. J Cardiovasc Electrophysiol. 1994, 5:933-944
[4] Szabo B, Rajagopalan CV, Lazzara R. The role of Na~+/ Ca~(2+) exchange in generation of early afterdpolarization in cardiac action potentials. FASEB J, 1992, 6:A1164
[5] Studer R, Reinecke H,Bilger J ey al. Gene expression of the Na~+/ Ca~(2+) exchange in end stage human heart failure. Circ Res.1994, 75:443-453
[6] Bum RC, Francis B, Guy S. Cytosolic Ca~(2+) triggers early afterdepolarization and Torsade de Pointes in rabbit heart with type 2 long QT syndrome. Journal of Physiology. 2002, 543(2):615-631
[7] Karin RS, Paul GA, Volder MA et al. Altered NCX activity in cardiac hypertrophy and heart failure: a new target for therapy. Carc Res. 2002, 53:782-805
[8] Elizabeth AW, Jane FA, Sharon NH et al. Reperfusion-induced Ins(1,4,5) P3 generation and arrhythmogenesis require activation of the Na~+/ Ca~(2+) exchange. J Moll Cell. Cardiol. 2001, 33:1961-1869
[9] Antzelevitch C. The M cell. Invited Editorial Comment. J Cardiovasc, Pharmacol Ther. 1997,2:73-76.
[10] Antzelevitch C, S Sicouri SH, Litovsky A et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cell. Circ Res. 1991,69: 1427-1449.
[11] Anyukhovsky EP, Sosunov EA, Cainullin RZ et al. The controversial M cell. J Cardiovasc, Electrophysiol. 1999, 10: 244-260
[12] Liu DW and Antzelevitch C. Characteristics of the delayed rectifier current (I_(kr) and I_(ks)) in canine ventricular epicardial, midmyocardial and endocardial myocytes: a weaker I_(ks) contributes to the longer action potential of the M cell. Circ Res. 1995:76:351-365
[13] Francis LB and Stuart MC. Dispersion of ventricular repolarization and refractory period. Carc Res, 2001, 50:10-23
[14] Kiyosue T and Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ, Res. 1989, 64:389-397
[15] Li CZ, Wang XD, Wang HW et al. Four types of late Na channel current in isolated ventricular myocytes with reference to their contribution to the lastingness of action potential plateau. Acta Physiol. Sinica. 1997,49:241-248
[16] Lesh MD, Pring M and Spear JF, Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study. Circ. Res. 1989.65: 1426-1440
[17] Massimiliano Z, Andrew EP, Yang L et al. Beat-to-beat repolarization variability in ventricular myocytes and its suppression by electrical coupling. Am J Physiol. Heart Circ Physiol. 2000, 278:677-687
[18] Blaustein MP and Lederer WJ. Sodium/calcium exchange: it's physiological implications. PhysiolRev. 1999, 79(3):763-854
[19] Conway SJ, Koushik SV. Cardiac sodium-calcium exchanger: a double-edged sword. Cardiovasc Res 2001, 51(2): 194-7
[20] Antzelevitch C. Ion channels and ventricular arrhythmogenesis. Cellular and ionic mechanisms underlying the Brugada syndrome. Curr Opin Cardiol 1999, 12:274-279
[21] Richard S,Leclercq F, Lemarie S et al. current in compensated hypertrophy and the heart failure. Cardiovasc Res. 1998, 37:300-311
[22] Goldhaber JI. Metabolism in normal and ischemic myocardium in the Myocardium. Langer GA(ed) 2nd. San Diego, CA, Academic Press. 1997,325-393
[23] Clapham DE, Shrier A and DeHaan RL. Junctional resistance and action potential delay between embryonic heart cell aggregates. J Gen Physiol. 1980, 75:633-654
[24] Konta TK, Ikeda M, Yamaki K et al, Significant of discordant ST alternans in ventricular fibrillation. Circulation. 1990,82: 2185-2189
[25] Smith JM, Sato N, Tanaka H et al. Electrical alternans and cardiac electrical instability. Circulation. 1988, 77:110-121
[26] Kay GN, Plumb VJ, Arciniegas JG et al. Torsades de pointes: The long-short initiating sequence and other clinical feature. Observations in 32 patients. J Am Coll Cardiol. 1990, 2:806-817
[27] Denker S, Lehman M, Mahmua R et al. Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol. 1984, 53:505-515
[28] El-Sherif N, Gough WB, Restivo M. Reentrant ventricular arrhythmias in the late myocardial infarction period. Mechanisms by which a short-long-short cardiac sequence facilitates the induction of reentry. Circulation. 1991, 83:268-278
[29] Wier WG. [Ca~(2+)]_ⅰ Transient during excitation-contaction coupling of mammalian heart, in Fozzard HA, Haber E, Jennings RB Katz AM, Morgan HE (eds): The Heart and Cardiovascular System, Ed 2. New York, Raven Press. 1991, 1223-1248
[30] Hilgemann DW. "Best estimates" of physiological Na/Ca exchange function: calcium conservation and the cardiac electrical cycle, in Zipes DP, Jalife J (eds): Cardiac Electrophysilogy. Saunders Co. 1990, 51-61
[31] Barcenas-Ruiz L, Wier WG. Voltage dependence of intracellular [Ca~(2+)]_ⅰ transient in guinea pig ventricular myocytes. Circ Res 1987, 61:148-154
[32] Fabiato A. Stimulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic recticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985, 85:291-320
[33] Szabo B, Kovacs T, Lazzara R. Cesium increases intracellular uptake of calcium and increases force development in cardiac
ventricular muscle during the evolution of early afterdepolarization. J Am Coll Cardiol. 1990, 15:77-79
[34] Belardinelli L, Isenberg G: Actions of adenosine and isoproterenol on isolate mammalian ventricular myocytes. Circ Res.1983,53:287-297
[35] Rosenberg RL, Hess P, Tsien RW. Cardiac calcium channels in planar lipid bilayers. L-type channel and calciumOpermeable channels open at negative membrane potentials. J Gen Physiol. 1988, 92:27-54
[36] Patterson E, Szabo B, Scherlag BJ et al. Realy and delayed afterdepolarizations associated with cesium chloride-induced arrhymias in the dog. J Cardiovasc Pharrnacol. 1990,15:323-331
[37] Bers DM. Species differences and the role of sodium-calcium exchange in cardiac muscle relaxation, in Blaustein MP, Dipolo R, Reeves JP (eds). Sodium calcium exchange. New York, Annals of New York Academy of Science, 1991,12:375-385
[38] Song Y, Belardinelli L. ATP promotes development of afterdepolarizations and triggered activity in cardiac myocytes. Am J Physiol. 1994, 267:2005-2011
[39] Perchenet L, Hinde AK, Patel KCR et al. Stimulation of NCX by the Beta-adrenergic/protein kinase . a pathway in guinea-pig ventricular myocytes at 37oC, Pflugers Arch. 2000, 439:822-828
[40] Eigel BN, Hadley RW. Antisense inhibition of NCX during anoxia/reoxygenation in ventricular myocytes. Am J Physiol. 2001, 281:2184-2190
[41] Kass RS, Tsien RW. Control of action potential duration by calcium ions in cardiac Purkinje fibers. J Gen Physiol. 1976, 67:599-617
[42] McC. Brooks C, Hoffman BF, Suckling EE, Orias O. The effects of heart rate, action of autonomic nerves and chemical mediators on cardiac excitability, in McC.Brooks C, Hoffman BF, Suckling EE, Orias O (eds). Excitability of the Heart. New York, Grune & Strstton, 1995, 21:221-222
[43] Bogdanov KY, Vinogadova TM, Lakatta EG et al. Sinoatrial nodal cell ryanodine receptor and NCX . Molecular partners in pacemaker regulation. Circ Res. 2001, 88:1254-1258
[44] Kohmoto O, Levi AJ, Brige JHB. Relation between reverse NCX and Sarcoplasmic reticulum calcium release in guinea pig ventricular cells. Circ Res. 1994,74:50-554
[45] Sipido KR, Voiders, PG, DeGroot SH et al. Enhanced Calcium release and NCX activity in hypertrophied canine ventricular myocytes. Potential link between contractile adaptation and arrhythmogenesis. Circulation, 2000, 102:2137-2144
[46] Blaustein MP, Lederer WJ. Sodium/calcium exchange: its physiological implications. Physiol Rev. 1999, 79:763-854
[47] Kimura J, Miyamae A, Noma. Identification of sodium calcium exchange current in single ventricular cells of guinea-pig. J physiol. 1987,384:199-222
[48] Janvier NC, Boyett MR. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res. 1996, 32:69-84
[49] Rigg L, Terrar DA. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sinoatrial node. Exp Physiol, 1996, 81:877-880
[50] Shigekawa M, Iwamoto T. Cardiac Na-Ca exchange: molecular and pharmacological aspects. Circ Res. 201, 88:864-876
[51] Lipp P, Schwaller B, Niggli E. Specific inhibition of Na-Ca exchange function by anti-sense oligodeoxynucleotides. FEBS Lett. 1995, 364:198-202
[52] Spipido KR, Volder PG, Vos MA, Verdonck F. Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res. 2002 , 53(4):782-805. Review.
[53] Houser SR, Piacentino V Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000, 32(9):1595-607. Review.
[54] Kubota I, Tomoike H, Han X, Sakurai K. The Na~+-Ca~(2+) exchanger contributes to beta-adrenoceptor mediated positive inotropy in mouse heart. Japanese Heart Journal. 2002, 43(4): 399-407
[55] Segers M, Le role des potentials tardifs du Coeur. Mem Acad R Med Belg Series Ⅱ, 1941, (1), fascile 7. 1-30
[56] Bezier E. The initiation of impulses in cardiac muscle. Am J Physiol. 1943, 138:273-282
[57] Davis LD. Effect of changes in cycle lenth on diastolic depolarization produced by ouabain in canine Purkinje fibers. Circ Res. 1973, 32:206-214
[58] Rose MR. Gelband H, Hoffman BF. Correlation between effects of ouabain on the canine electrocardiogram and transmembrane potentials of isolated Purkinje fibers. Circulation. 1973, 47:65-72
[59] Cranefield P. Action potentials, afterpotentials and arrhythmias. Circ Res. 1977, 41:415-423
[60] Brachmann J, Scherlag BJ, Rosenshtraukh LV, Lazzara R. Bradycardia-dependent triggered activity: relevance to druginduced multiform ventricular tachycardia. Circulation. 1983, 68:846-856
[61] Volder PG, Kulscar A, Vos MA et al. Similarities between early and delayed afterdepolarizations induced by isoproterenol
in canine ventricular myocytes. Cardiovasc Res. 1997, 34: 348-359
[62] Janury CT, Riddle JM, Salata JJ. A model for early afterdepolarizations: Mechanism of induction and block: a role for L-type Ca~(2+) current. Circ Res. 1989, 64:977-990
[63] Zeng J, Rudy Y. Early afterdepolarization in cardiac myocytes: mechanism and rate dependence. Biophys J. 1995, 68:949-964
[64] Szabo B, Sweidan R, Rajagopalan CV, Lazzara R. Role of NCX current in Cs~+-induced early afterdepolarizations in Purkinje fibers. J Cardiovasc Electrophysiol, 1994, 5:933-944
[65] Szabo B, Kovacs T, Lazzara R. Role of calcium loading in early afterdepolarizations generated by Cs~+ in canine and guinea pig Purkinje fibers. J Cardiovasc Electrophysiol. 1995, 6:796-812
[66] Shimizu W, Ohe T, Kurita T et al. Epinephrine-induced ventricular premature complete atriventricular block and torsade de pointes. Pacing Clin Electrophysiol. 1993, 126:33-38
[67] Sato T, Hata Y, Yamamoto M et al. Early afterdepolarization abolished by potassium channel opener in a patient with idiopathic long QT syndrome. J Cardiovasc Electrophysiol. 1995, 6:279-282
[68] Shimizu W, Kurita T, Matsuo K et al. Improvement of repolarization abnormalities by a K~+ channel opener in the LQTS form of congenital long-QT ayndrome. Circulation. 1998,97:1581-158
[69] Spitzer KW, Sato H, Tanaka L et al. Electrotonic modulation of electrical activity in rabbit strioventricular node myocytes. Am J Physiol. Heart Circ Physiol. 1997,273:767-776
[70] Babij PG, Askew B, Nieuwenhuijsen CM et al. Inhibition of cardiac delayed rectifier K~+ current by overexpression of the
long-QT syndrome HERG G628S mutation in transgenic mice. Circ Res. 1998, 83:668-678
[71] Sanguinetti MC, Jiang C, Curran ME et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the Ikr potassium channel. Cell. 1995, 81: 299-307
[72] Saiz J, Ferrero JM, Monserrat M et al. Influence of electrical coupling on early afterdepolarizations in ventricular myocytes. IEEE Trans. Biomed Eng. 1999, 46:138-147
[73] Wilders R and Jongsma HJ. Beating irregularity of single pacemaker cells isolated from the rabbit sinoatial node. Biophys J. 1993, 65:2601-2613
[74] Liu YL, Defelice J and Mazzanti M. Sodiom channels that remain open throughout the cardiac action potential plateau. Biophys J. 1992:63:645-662
[75] Kiyosue T and Arita M. Late sodium current and its contribu-tion to action potential configuration in guinea pig ventricular myocytes. Circ Res. 1989, 64:389-397
[76] Li CZ, Wang XD, Wang HW et al. Four types of late Na channel current in isolated ventricular myocytes with reference to their contribution to the lastingness of action potential plateau. Acta Physiol. Sinica. 1997, 49:241-248
[77] Huelsing DJ, Spitzer KW, Cordeiro JM et al. Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol. Heart Circ Physiol. 1998, 274:1163-1173
[78] Huelsing DJ, Spitzer KW, Cordeiro JM et al. Modulation of repolarization in rabbit Purkinje and ventricular myocytes coupled by a variable resistance. Am J Physiol. Heart Circ Physiol. 1999, 276:572-581
[79] Liu DW, Gitant GA and Antzelevitch C. Ionic bases for electrophysiologieal distinctions among epicardial, midmyocardial and endocardial myocytes from the free wall of the canine left ventricle. Cite Res. 1993, 72:671-687
[80] You YD, Pelzer J and Pelzer S. Modulation of L-type calcium current by fast and slow calcium buffering in guinea pig ventricular cardiomyocytes. Biophys. 1997,72: 175-187
[81] Cheng MB, Cheng BH and Lederer WJ. Spatial non-uniformities in Ca during excitation-contraction coupling in cardiac myocytes.
[82] Cheng H, Lederer WJ and Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993, 262:740-744
[83] Lopez-Lopez J, Schackloek PS, Balke CW et al. Local stochastic release of Ca~(2+) in voltage clamped rat heart cells: visualization with confocal microscopy. J Physiol (Lond). 1994, 480:21-29
[84] Goldman Y, Morad M. Ionic membrane conductance during the time course of the cardiac action potential. J Physiol(Lond). 1997, 268:655-695
[85] Weidmann S. Effect of current flow on the membrane potential of cardiac muscle. J Physiol. (Lond), 1991, 115:227-236
[86] Wagner JA, Weisman HF, Snowman AM et al Alterations in calcium antagonist receptors and sodium-calcium exchange in cardiomyopathic hamster tissues. Circ Res. 1989, 65:205-214
[87] David DM, Pernollet MG, LeQuan SH et al. Active Na~+ and Ca~(2+) transport, Na~+ -Ca~(2+) exchange and intracellular Ca~(2+) and Na~+ content in young spontaneously hypertensive rats. J Cardiovase Phamacol. 1986, 8:130-135
[88] Nakanishi H, Makino N, Hata T et al. Sarcolemmal Ca~(2+) transport activities in cardiac hypertrophy caused by pressure overload. Am J Physiol, 1989, 257:349-356
[89] Brooks WW, Bing OH, Boluyt MO et al. Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. Hypertension. 2000, 35:1203-1209
[90] Andrawis NS, Kou TH, Giacomelli F et al. Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. J Mol Cell Cardiol.1988, 20:625-634
[91] Naqvi RU, Macleod KT, Effect of hypertrophy on mechanisms of relaxation in isolated cardiac myocytes from guinea pig. Am J Physiol. 1994, 267:1851-1861
[92] Heyliger CE, Takeo S, Dhalla NS. Alteration in sarcolemmal Na~+ -Ca~(2+) exchange
[93] McCall E, Ginsburg KS, Bassani RA et al. Ca flux contractility and excitation- contraction coupling in hpertrophic rat ventricular myocytes. Am J Physiol. 1998, 274:1346-1360
[94] Wang Z, Nolan B, Kutschke W, Hill JA. Na~+ -Ca~(2+) exchange remodeling in pressure-overload cardiac Hypertrophy. J Biol Chem. 2001, 276:177706-17711
[95] Vos MA, de Groot SH, Verduyn SC et al. Enhanced susceptibility for acquired torsade de points arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation. 1998, 98:1125-1135
[96] Sipido KR, Volder PGA, Groot SH et al. Enhanced Ca~(2+) release and Na~+ -Ca~(2+) exchange activity in hypertrophied canine ventricular myocytes: a potential link between contractile adaptation and arrhymogenesis. Circulation, 2000, 102:2137-2144
[97] Verdonck F, Voider PGA, Vos MA et al. Cardiac hypertrophy is associated with an increase in subsarcolemmal Na~+ .Biophys J. 2001, 80:589
[98] Volders PGA, Sipido KR, Vos MA et al Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation, 1998, 98:1136-1147
[99] Volders PGA, Sipido KR, Vos MA et al. Downregulation of delayed rectified K current in dogs with chronic complete atrioventricular block and acquired torsades de point, Circ Res, 1999, 84:562-570
[100] O'Rourke B, Kass DA, Tomaselli GF et al. Mechanisms of altered excitation-contraction coupling in canine tachycardiainduced heart failure. Experiment studies. Circ Res, 1999,84:562-570
[101] Yao A, Su Z, Nonaka A et al. Abnormal myocyte homeostasis in rabbits with pacing-induced heart failure. Am J Physiol. 1998, 87:690-698
[102] Tsuji Y, Opthof T, Kamiya K et al. Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreased in calcium and transient outward current in rabbit ventricle. Cardiovasc Res. 2000, 48:300-309
[103] Vermeulen JT, McGuire MA, Opthof T et al. Triggered activity and automaticity in ventricular traceculae of failing human and rabbit hearts. Cardiovasc Res. 1994, 28:1547-1554
[104] Pogwizd SM. Nonreentrant mechanisms underlying spontaneous ventricular srrhythmias in a model of nonischemic heart failure in rabbits. Circulation. 1995, 92:1034-1048
[105] Aygmunt AC, Goodrow RJ, Antzelevitch C. I_(NCX) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol. 2000, 278:1671-1678
[106] Matiello JA, Margulies KB, Jeevanandam V et al. Contribution of reverse mode sodiumpcalcium exchange to contractions in failing human left ventricular myocyte. Cardiovasc res. 1998, 37:424-431
[107] Gaughan JPm Furukawa S, Jeevanandam V et al. Sodium/calcium exchange contributes to contraction and relaxation in failed human ventricular myocytes. Am J Physiol. 1999, 277: 714-724
[108] Dipla K, Mattiello JA, Margulies KB et al. The sarcoplasmic recticulum and the Na~+ -Ca~(2+) exchange both contribute to the Ca~(2+) transient of failing human ventricular myocytes. Circ Res. 1999, 84:435-444
[109] Iwamoto T, Watano T, Shigekawa M. A novel isothiourea derivative selectively inhibits the reverse mode of Na~+ -Ca~(2+) exchange in cells expressing NCX1, J Biol Chem. 1996, 271:22391-22397
[110] Kimura J, Watano T, Shigekawa M et al. Direction-independent block of Na~+ -Ca~(2+) exchange bi-directional current by KBR7943 in guinea-pig cardiac myoeytes. Br J Pharmacol. 1999, 128:969-974
[111] Heerdt PM, Holmes JW, Cai B et al. Chronic unloading by left ventricular assit device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000, 102:2713-2791