钠氢交换抑制剂Cariporide对家兔心房电重构的影响
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摘要
前言
心房颤动(房颤)是十分常见的心律失常。其群体发病率约为0.4％～0.9％，它的危险度随年龄的增加而升高。房颤分为阵发性房颤、持续性房颤和永久性房颤，后两者又称为慢性房颤。阵发性房颤常发展为慢性房颤，其转化率随病因而有所差异。在发展为慢性房颤的因素中，阵发性房颤的持续时间是关键的。在阵发性房颤的持续时间小于2天的患者中有31％将转为慢性，而如果阵发性房颤的持续时间更长，这个数值将会高达46％。
对于阵发性房颤发展为慢性房颤者，可能存在某种机制使颤动波维持稳定或终止后很快复发。Katz等将心房颤动对心脏的影响分为3个基本方面：①代谢改变(细胞)；②离子通道改变(基因)；③结构改变(器官)。代谢适应过程发生最快，一般在心率改变的数秒至数分内即出现，细胞内离子浓度、离子泵活性、离子通道的磷酸化程度发生变化。当心率改变持续数小时或数天时，会出现电重构。当房颤持续数周后，心房肌细胞会发生结构改变，若持续更长时间，则心房肌细胞产生不可逆的结构破坏。
房颤所引起的心房电重构是维持房颤自身延续并发展为持续性房颤的主要原因之一，即所谓的房颤导致房颤作用(Atrial Fibrillation Begets Atrial Fibrillation)。而房颤所引起的结构重构为持续性房颤转复窦律后心房肌收缩功能抑制的重要原因。因此目前研究认为房颤的电重构和结构重构是房颤的两个最重要特征。
研究已证明，钠氢交换体1型(NHE-1)参与了心肌细胞内的钙的调节过程，NHE-1的激活是心房短期电重构和结构重构的机制之一。有证据表明，短期房颤心房肌因存在氧供需失衡，可能存在细胞内酸中毒，使用钠氢交换体抑制剂
浙江大学硕士学位论文
(NHEIs)可阻止细胞内酸中毒引起的钠超载及继发性的钙超载而阻止电重构的发
生。
目前，国内尚无NHEI在房颇心房电重构方面作用的动物实验或临床试验的相
关报道。本研究的目的在于研究NHE一1特异性抑制剂cariporide对家兔心房快速
起搏所致的心房电重构的影响，并推断钠氢交换体1型在急性房颤心房电重构中
可能的作用。
材料和方法
1、研究对象:
健康成年家兔20只，雌雄不限，体重2.2~2.gkg，随机分为两组。对照组在
心房起搏前注射DMso注射液(溶剂)，NHEI组在心房起搏前注射Cariporide注
射液。
2、主要仪器和试剂:
cF一4型多功能心脏电生理程控刺激仪、EP Laboratory Labsystem DUO多导电
生理记录仪、DSA、Cordis电极、一次性静切包、静脉拉钩、微量注射泵、微量移
液器、cariPoride、DMso、乌来糖(乌拉坦)、酒石酸美托洛尔注射液、盐酸阿托
品注射液
3、实验方法
家兔以20%乌来糖溶液1叭g耳缘静脉注射麻醉，仰卧固定，以针状电极接
体表心电图。分离右侧颈外静脉和颈内静脉，分别置入电极用于心房起搏和描记
心房电位。将描记电极接于多导生理仪，将起搏电极接于程控刺激仪，以脉宽Zms
测定起搏闽值，设定2倍起搏闽值为输出电压。通过耳缘静脉注射Cariporide
(Zm叭g)或等量的溶剂。同时注射美托洛尔(0 .2m叭g)及阿托品(0 .04m叭g)
以阻断自主神经对心脏的影响，并以微量注射泵维持(美托洛尔0.02mg·k扩·h’’，
阿托品0.o07mg·kg一’·E’)。在注射药物后十五分钟，记录窦性心率，以程控刺激
法，步长sms反扫，起搏周期(orive Cyele Length，DCL)为Zooms，15oms，13oms，
分别测定AE即(AERP200，AERP:50，AERP;30)。以600bPm固定频率进行快速心
房起搏，于刺激后0.5，1，2，4，6小时重复测定心率及AERP。
浙江大学硕士学位论文
4、统计学分析
去除未完成6小时起搏的家兔的数据。所有数据均以均数土标准差表示，统
计分析使用SPSS vl 1.0软件进行处理。对照组和NHEI组之间采用独立样本t检验。
对照组和NHEI组组内不同起搏时间点之间进行单因素方差分析(one一way
ANOVA)。
结果
1、对照组起搏后AERP较起搏前明显缩短，AERPZ。。相对变化量在起搏后1
小时及以后与起搏前相比均存在显著差异(P<0 .05)。NHEI组的各起搏时间点之
间的心率和AE即均无显著差异。
2、与对照组相比，NHEI组起搏后AE即2。。相对变化量缩短较对照组显著减
少(P<0 .05)。
3、对照组和NHEI组的组内和组间的心率均无显著差异。
4、对照组在起搏后频率适应性下降，起搏前AERP.3。较AERP20。短
n.88士15.57ms，而起搏后6小时只短了4.38士5.63ms。而NHEI组在起搏后频率适
应性并未发生显著变化。
结论
1、快速心房起搏可以导致心房有效不应期的缩短，在较长的起搏周长时这种效应
更明显。
2、cariPoride可有效抑制快速心房起搏导致的心房有效不应期的缩短，在较长的
起搏周长时这种效应更明显。
3、CariPoride能够阻止快速心房起搏导致的AE即频率适应性下降。
4、快速心房起搏和Cariporide对窦性自主心率均无显著影响。
Background
Atrial fibrillation (AF) is a common arrhythmia with a prevalence of 0.4% to 0.9% in the population. Its incidence increases with age. The course of atrial fibrillation can be classified to paroxysmal atrial fibrillation and chronic atrial fibrillation (including persistent atrial fibrillation and permanent atrial fibrillation). Most of patients with paroxysmal atrial fibrillation often progresses to chronic atrial fibrillation with different transform ratio by different pathogenesis. The duration of the paroxysms of atrial fibrillation was found to be of importance, transition to chronic atrial fibrillation occurring in 31% of patients with paroxysms shorter than 2 days versus 46% if the episodes of atrial fibrillation were of longer duration.
There may be a mechanism to maintain atrial fibrillation or relapse during the course from paroxysmal atrial fibrillation to chronic atrial fibrillation. Katz's divided the influence of heart by atrial fibrillation into three types, they are metabolic change (on the cell), ion channel change (on the gene) and structure change (on the organ). The fastest change is on the metabolism which occurs from a few seconds to a few minutes. The ion concentration in the cells, the activity of ion pump and the phosphorylation of ion channel will be changed. And the electrophysiological remodeling will happen
when the atrial fibrillation sustains a few hours or a few days. The atrial myocardium cells will remodel after a few weeks. Then long-term atrial fibrillation will cause irreversible structure destroy.
The electrophysiological remodeling caused by atrial fibrillation is one of the reasons which beget the maintain of atrial fibrillation and develop to the sustained atrial fibrillation. It's just called "Atrial Fibrillation Begets Atrial Fibrillation". And the structure remodeling caused by atrial fibrillation is an important factor which leads the atrial contractile dysfunction after sustain atrial fibrillation defibrillation. So in recent studies indicate that the electrophysiological and structure remodeling is the most character of atrial fibrillation.
Previous studies show that the Na+/H+ Exchanger subtype 1 (NHE-1) take part into the regulation of Calcium in the myocardium cells, and the activity of NHE-1 is one of the mechanisms of the short-term electrophysiological remodeling and the structure remodeling. Some evidence indicates that atrial myocardium cells have intracellular acidosis because is hypoxia during short-term atrial fibrillation. The Na+/H+ Exchanger Inhibitors (NHEIs) prevent the Na+ overload and the secondary Ca2+ overload caused by intracellular acidosis. So it prevents the electrophysiological remodeling.
There is no report about atrial eletrophysiological remodeling effects of NHEI. The purpose of this study was to test the atrial electrophysiological remodeling effects of Cariporide, a selective blockade of the cardiac NHE-1 isoform, in short-term rapid atrial pacing on rabbit, and suspect the mechanism of NHE-1 in atrial electrophysiological remodeling. Materials and Methods 1, Study subjects
Twenty adult rabbits (2.2 to 2.9 kg) were selected. The control group was injected the solvent of Cariporide, and the experimental group was injected the Cariporide.
2 Equipment and reagent
CF-4 multifunction cardiac electrophysiological programmed stimulator, EP Laboratory LabSystem DUO multi-channel electrophysiological recorder, DSA, Cordis electrode catheter, Venous hook, Injection micro pump, Transfer micro pipe, Cariporide, DMSO, Urethane, Metoprolol tartaric acid, atropine hydrochloride, 3 Methods
Rabbit was anesthetized with a bolus dose of 20% urethane (5ml/kg IV) and fixed on the operation table. The internal jugular vein and external jugular vein were isolated, and two Cordis electrode catheter were insert into the right atrium via them. One is used to pace right atrium, another is used to record right atrium electrogram. Next, the recording electrode was connected to the multi-channel electrophysiological and the pac
心房颤动(房颤)是十分常见的心律失常。其群体发病率约为0.4％～0.9％，它的危险度随年龄的增加而升高。房颤分为阵发性房颤、持续性房颤和永久性房颤，后两者又称为慢性房颤。阵发性房颤常发展为慢性房颤，其转化率随病因而有所差异。在发展为慢性房颤的因素中，阵发性房颤的持续时间是关键的。在阵发性房颤的持续时间小于2天的患者中有31％将转为慢性，而如果阵发性房颤的持续时间更长，这个数值将会高达46％。
对于阵发性房颤发展为慢性房颤者，可能存在某种机制使颤动波维持稳定或终止后很快复发。Katz等将心房颤动对心脏的影响分为3个基本方面：①代谢改变(细胞)；②离子通道改变(基因)；③结构改变(器官)。代谢适应过程发生最快，一般在心率改变的数秒至数分内即出现，细胞内离子浓度、离子泵活性、离子通道的磷酸化程度发生变化。当心率改变持续数小时或数天时，会出现电重构。当房颤持续数周后，心房肌细胞会发生结构改变，若持续更长时间，则心房肌细胞产生不可逆的结构破坏。
房颤所引起的心房电重构是维持房颤自身延续并发展为持续性房颤的主要原因之一，即所谓的房颤导致房颤作用(Atrial Fibrillation Begets Atrial Fibrillation)。而房颤所引起的结构重构为持续性房颤转复窦律后心房肌收缩功能抑制的重要原因。因此目前研究认为房颤的电重构和结构重构是房颤的两个最重要特征。
研究已证明，钠氢交换体1型(NHE-1)参与了心肌细胞内的钙的调节过程，NHE-1的激活是心房短期电重构和结构重构的机制之一。有证据表明，短期房颤心房肌因存在氧供需失衡，可能存在细胞内酸中毒，使用钠氢交换体抑制剂
浙江大学硕士学位论文
(NHEIs)可阻止细胞内酸中毒引起的钠超载及继发性的钙超载而阻止电重构的发
生。
目前，国内尚无NHEI在房颇心房电重构方面作用的动物实验或临床试验的相
关报道。本研究的目的在于研究NHE一1特异性抑制剂cariporide对家兔心房快速
起搏所致的心房电重构的影响，并推断钠氢交换体1型在急性房颤心房电重构中
可能的作用。
材料和方法
1、研究对象:
健康成年家兔20只，雌雄不限，体重2.2~2.gkg，随机分为两组。对照组在
心房起搏前注射DMso注射液(溶剂)，NHEI组在心房起搏前注射Cariporide注
射液。
2、主要仪器和试剂:
cF一4型多功能心脏电生理程控刺激仪、EP Laboratory Labsystem DUO多导电
生理记录仪、DSA、Cordis电极、一次性静切包、静脉拉钩、微量注射泵、微量移
液器、cariPoride、DMso、乌来糖(乌拉坦)、酒石酸美托洛尔注射液、盐酸阿托
品注射液
3、实验方法
家兔以20%乌来糖溶液1叭g耳缘静脉注射麻醉，仰卧固定，以针状电极接
体表心电图。分离右侧颈外静脉和颈内静脉，分别置入电极用于心房起搏和描记
心房电位。将描记电极接于多导生理仪，将起搏电极接于程控刺激仪，以脉宽Zms
测定起搏闽值，设定2倍起搏闽值为输出电压。通过耳缘静脉注射Cariporide
(Zm叭g)或等量的溶剂。同时注射美托洛尔(0 .2m叭g)及阿托品(0 .04m叭g)
以阻断自主神经对心脏的影响，并以微量注射泵维持(美托洛尔0.02mg·k扩·h’’，
阿托品0.o07mg·kg一’·E’)。在注射药物后十五分钟，记录窦性心率，以程控刺激
法，步长sms反扫，起搏周期(orive Cyele Length，DCL)为Zooms，15oms，13oms，
分别测定AE即(AERP200，AERP:50，AERP;30)。以600bPm固定频率进行快速心
房起搏，于刺激后0.5，1，2，4，6小时重复测定心率及AERP。
浙江大学硕士学位论文
4、统计学分析
去除未完成6小时起搏的家兔的数据。所有数据均以均数土标准差表示，统
计分析使用SPSS vl 1.0软件进行处理。对照组和NHEI组之间采用独立样本t检验。
对照组和NHEI组组内不同起搏时间点之间进行单因素方差分析(one一way
ANOVA)。
结果
1、对照组起搏后AERP较起搏前明显缩短，AERPZ。。相对变化量在起搏后1
小时及以后与起搏前相比均存在显著差异(P<0 .05)。NHEI组的各起搏时间点之
间的心率和AE即均无显著差异。
2、与对照组相比，NHEI组起搏后AE即2。。相对变化量缩短较对照组显著减
少(P<0 .05)。
3、对照组和NHEI组的组内和组间的心率均无显著差异。
4、对照组在起搏后频率适应性下降，起搏前AERP.3。较AERP20。短
n.88士15.57ms，而起搏后6小时只短了4.38士5.63ms。而NHEI组在起搏后频率适
应性并未发生显著变化。
结论
1、快速心房起搏可以导致心房有效不应期的缩短，在较长的起搏周长时这种效应
更明显。
2、cariPoride可有效抑制快速心房起搏导致的心房有效不应期的缩短，在较长的
起搏周长时这种效应更明显。
3、CariPoride能够阻止快速心房起搏导致的AE即频率适应性下降。
4、快速心房起搏和Cariporide对窦性自主心率均无显著影响。
Background
Atrial fibrillation (AF) is a common arrhythmia with a prevalence of 0.4% to 0.9% in the population. Its incidence increases with age. The course of atrial fibrillation can be classified to paroxysmal atrial fibrillation and chronic atrial fibrillation (including persistent atrial fibrillation and permanent atrial fibrillation). Most of patients with paroxysmal atrial fibrillation often progresses to chronic atrial fibrillation with different transform ratio by different pathogenesis. The duration of the paroxysms of atrial fibrillation was found to be of importance, transition to chronic atrial fibrillation occurring in 31% of patients with paroxysms shorter than 2 days versus 46% if the episodes of atrial fibrillation were of longer duration.
There may be a mechanism to maintain atrial fibrillation or relapse during the course from paroxysmal atrial fibrillation to chronic atrial fibrillation. Katz's divided the influence of heart by atrial fibrillation into three types, they are metabolic change (on the cell), ion channel change (on the gene) and structure change (on the organ). The fastest change is on the metabolism which occurs from a few seconds to a few minutes. The ion concentration in the cells, the activity of ion pump and the phosphorylation of ion channel will be changed. And the electrophysiological remodeling will happen
when the atrial fibrillation sustains a few hours or a few days. The atrial myocardium cells will remodel after a few weeks. Then long-term atrial fibrillation will cause irreversible structure destroy.
The electrophysiological remodeling caused by atrial fibrillation is one of the reasons which beget the maintain of atrial fibrillation and develop to the sustained atrial fibrillation. It's just called "Atrial Fibrillation Begets Atrial Fibrillation". And the structure remodeling caused by atrial fibrillation is an important factor which leads the atrial contractile dysfunction after sustain atrial fibrillation defibrillation. So in recent studies indicate that the electrophysiological and structure remodeling is the most character of atrial fibrillation.
Previous studies show that the Na+/H+ Exchanger subtype 1 (NHE-1) take part into the regulation of Calcium in the myocardium cells, and the activity of NHE-1 is one of the mechanisms of the short-term electrophysiological remodeling and the structure remodeling. Some evidence indicates that atrial myocardium cells have intracellular acidosis because is hypoxia during short-term atrial fibrillation. The Na+/H+ Exchanger Inhibitors (NHEIs) prevent the Na+ overload and the secondary Ca2+ overload caused by intracellular acidosis. So it prevents the electrophysiological remodeling.
There is no report about atrial eletrophysiological remodeling effects of NHEI. The purpose of this study was to test the atrial electrophysiological remodeling effects of Cariporide, a selective blockade of the cardiac NHE-1 isoform, in short-term rapid atrial pacing on rabbit, and suspect the mechanism of NHE-1 in atrial electrophysiological remodeling. Materials and Methods 1, Study subjects
Twenty adult rabbits (2.2 to 2.9 kg) were selected. The control group was injected the solvent of Cariporide, and the experimental group was injected the Cariporide.
2 Equipment and reagent
CF-4 multifunction cardiac electrophysiological programmed stimulator, EP Laboratory LabSystem DUO multi-channel electrophysiological recorder, DSA, Cordis electrode catheter, Venous hook, Injection micro pump, Transfer micro pipe, Cariporide, DMSO, Urethane, Metoprolol tartaric acid, atropine hydrochloride, 3 Methods
Rabbit was anesthetized with a bolus dose of 20% urethane (5ml/kg IV) and fixed on the operation table. The internal jugular vein and external jugular vein were isolated, and two Cordis electrode catheter were insert into the right atrium via them. One is used to pace right atrium, another is used to record right atrium electrogram. Next, the recording electrode was connected to the multi-channel electrophysiological and the pac
引文
[1] Wiffels M, Kirchhof C, Dorland R, et al. Atrial Fibriilation Begets Atrial Fibirllation: A Study in Awake Chronically Instrumented Goats [J]. Circulation, 1995, 92:1954-1968.
[2] 沈潞华。心房颤动的药物治疗[J]。北京医学，2003，25(3)：202-204。
[3] 李洪波，陈润芬，黄定九。心房颤动对心房肌细胞的影响[J]。心脏杂志，2002，1 4(3)：252-254。
[4] Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrllation treated by discrete radiofreqency ablation [J]. Circulation, 1997, 95(3): 572-576.
[5] Allessie MA, Konings K, Kirchhof CJ, et al. Electrophysiologic mechanisms of perpetuation atrial fibrillation [J]. Am J Cardiol, 1996, 77(3): 10A-23A.
[6] Moe GK. On the multiple wavelet hypothesis of atrial fibrillation [J]. Arch Int Pharmaeodyn Ther, 1962, 140:183-188.
[7] Hobbs WJ, van-Gelder IC, Fitzpatrick AP, et al. The role of atrial electrical remodeling in the progression of focal atrial ectopy to persist atrial fibrillation [J]. J Cardiovase Electrophysiol, 1999, 10:866-870.
[8] Gaspo R, Bosch RF, bou-Abboud E, et al. Tachycarida-induced changes in Na+ current in a chronic dog model of atrial fibrillation [J]. Citc Res, 1997, 81:1045-1052.
[9] van-Gelder IC, Brundel B J, Henning RH, et al. Alterations in gene expression of proteins involved in the calcium handling in patients with atrial fibrillation [J]. J Cardiovase Electrophysiol, 1999, 10:552-560.
[10] Yamashita T, Murakawa Y, Hayami N, et al. Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium: Electrical Remodeling in Paroxysmal Atrial Tachycardia [J]. Circulation, 2000,101:2007-2014.
[11] Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation [J]. Circ Res, 1999, 85:428-436.
[12] Yu WC, Chen SA, Lee SH, et al. Tachycardia-induced change of atrial refreactory
period in humans: Rate-dependency and effects of antiarrhythmic drugs [J]. Circulation, 1998, 97:2331-2337.
[13] Daoud EG, Knight BP, Weiss R, et al. Effect of Verapamil and Procainamide on atrial fibrillation - induced electrical remodeling in humans [J]. Circulation, 1997, 96:1542-1550.
[14] Masereel B, Pochet L, Laeckmann D. An overview of inhibitors ofNa+/H+ exchanger [J]. Eur J Med Chem, 2003, 38(6): 547-554.
[15] Menown IB, Adgey AA. Cardioprotective Therapy and Sodium-Hydrogen Exchange Inhibition: Current Concepts and Future Goals [J]. J Am Coil Cardiol, 2001, 38(6): 1651-1653.
[16] Levitsky J, Gurell D, Frishman WH. Sodium Ion/Hydrogen Ion Exchange Inhibition: A New Pharmacologic Approach to Myocardial Ischemia and Reperfusion Injury [J]. J Clin Pharmaeoi, 1998, 38(10): 887-897.
[17] Aye NN, Xue YX, Hashimoto K. Antiarrhythmic effects of cariporide, a novel Na~+-H~+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts [J]. Eur J Pharmacol, 1997, 339 (2-3): 121-127.
[18] White CW, Kerber RE, Weiss HR, et al. The effects of atrial fibrillation on atrial pressure-volume and flow relationship [J]. Cire Res, 1982, 51:205-215.
[19] Aye NN, Komori S, Hashimoto K. Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo [J]. Br J Pharmacol, 1999, 127(4): 1048-1055.
[20] Gazmuri R J, Ayoub IM, Hoffner E, et al. Successful Ventdcular Defibrillation by the Selective Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Cariporide [J]. Circulation, 2001, 104(2): 234-239.
[21] Gumina RJ, Daemmgen J, Gross GJ. inhibition of the Na~+/H~+ exchanger .attenuates phase lb ischemic arrhythmias and reperfusion-induced ventricular fibrillation[J]. Eur J Pharmacol, 2000, 396(2-3): 119-124.
[22] Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na~+/H~+ Exchanger in Short-Term Atrial Electrophysiological Remodeling [J]. Circulation, 2000, 101 (15): 1861-1866.
[2] 沈潞华。心房颤动的药物治疗[J]。北京医学，2003，25(3)：202-204。
[3] 李洪波，陈润芬，黄定九。心房颤动对心房肌细胞的影响[J]。心脏杂志，2002，1 4(3)：252-254。
[4] Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrllation treated by discrete radiofreqency ablation [J]. Circulation, 1997, 95(3): 572-576.
[5] Allessie MA, Konings K, Kirchhof CJ, et al. Electrophysiologic mechanisms of perpetuation atrial fibrillation [J]. Am J Cardiol, 1996, 77(3): 10A-23A.
[6] Moe GK. On the multiple wavelet hypothesis of atrial fibrillation [J]. Arch Int Pharmaeodyn Ther, 1962, 140:183-188.
[7] Hobbs WJ, van-Gelder IC, Fitzpatrick AP, et al. The role of atrial electrical remodeling in the progression of focal atrial ectopy to persist atrial fibrillation [J]. J Cardiovase Electrophysiol, 1999, 10:866-870.
[8] Gaspo R, Bosch RF, bou-Abboud E, et al. Tachycarida-induced changes in Na+ current in a chronic dog model of atrial fibrillation [J]. Citc Res, 1997, 81:1045-1052.
[9] van-Gelder IC, Brundel B J, Henning RH, et al. Alterations in gene expression of proteins involved in the calcium handling in patients with atrial fibrillation [J]. J Cardiovase Electrophysiol, 1999, 10:552-560.
[10] Yamashita T, Murakawa Y, Hayami N, et al. Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium: Electrical Remodeling in Paroxysmal Atrial Tachycardia [J]. Circulation, 2000,101:2007-2014.
[11] Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation [J]. Circ Res, 1999, 85:428-436.
[12] Yu WC, Chen SA, Lee SH, et al. Tachycardia-induced change of atrial refreactory
period in humans: Rate-dependency and effects of antiarrhythmic drugs [J]. Circulation, 1998, 97:2331-2337.
[13] Daoud EG, Knight BP, Weiss R, et al. Effect of Verapamil and Procainamide on atrial fibrillation - induced electrical remodeling in humans [J]. Circulation, 1997, 96:1542-1550.
[14] Masereel B, Pochet L, Laeckmann D. An overview of inhibitors ofNa+/H+ exchanger [J]. Eur J Med Chem, 2003, 38(6): 547-554.
[15] Menown IB, Adgey AA. Cardioprotective Therapy and Sodium-Hydrogen Exchange Inhibition: Current Concepts and Future Goals [J]. J Am Coil Cardiol, 2001, 38(6): 1651-1653.
[16] Levitsky J, Gurell D, Frishman WH. Sodium Ion/Hydrogen Ion Exchange Inhibition: A New Pharmacologic Approach to Myocardial Ischemia and Reperfusion Injury [J]. J Clin Pharmaeoi, 1998, 38(10): 887-897.
[17] Aye NN, Xue YX, Hashimoto K. Antiarrhythmic effects of cariporide, a novel Na~+-H~+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts [J]. Eur J Pharmacol, 1997, 339 (2-3): 121-127.
[18] White CW, Kerber RE, Weiss HR, et al. The effects of atrial fibrillation on atrial pressure-volume and flow relationship [J]. Cire Res, 1982, 51:205-215.
[19] Aye NN, Komori S, Hashimoto K. Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo [J]. Br J Pharmacol, 1999, 127(4): 1048-1055.
[20] Gazmuri R J, Ayoub IM, Hoffner E, et al. Successful Ventdcular Defibrillation by the Selective Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Cariporide [J]. Circulation, 2001, 104(2): 234-239.
[21] Gumina RJ, Daemmgen J, Gross GJ. inhibition of the Na~+/H~+ exchanger .attenuates phase lb ischemic arrhythmias and reperfusion-induced ventricular fibrillation[J]. Eur J Pharmacol, 2000, 396(2-3): 119-124.
[22] Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na~+/H~+ Exchanger in Short-Term Atrial Electrophysiological Remodeling [J]. Circulation, 2000, 101 (15): 1861-1866.