新药盐酸关附甲素抗心律失常作用的实验和临床研究
|
摘要
第一部分：盐酸关附甲素对大鼠心室肌细胞膜L型钙通道(I_(Ca-L))的影响
目的：研究盐酸关附甲素对正常大鼠心室肌细胞L型钙离子通道(I(Ca-L))的影响、旨在探讨其抗心律失常作用机制。
方法：应用经典方法酶解分离大鼠单个心室肌细胞。应用膜片钳全细胞记录方法，维持电位Vh=-50mV，刺激脉冲从-40mV～+50mV诱发出L型钙电流，记录关附甲素对I(Ca-L)的作用并对通道动力学作出初步评价。
结果：1．关附甲素呈浓度依赖性阻断I(Ca-L)，在25、125、250、1000μM时I(Ca-L)峰值电流密度(去极化至0mV时)分别减少为用药前的81.76％、77.54％、76.46％、64.77％，P＜0.05。2．关附甲素使I(Ca-L) Ⅰ-Ⅴ曲线上移，但不改变其激活电位、峰值电位。3．关附甲素呈轻度使用依赖性阻滞I(Ca-L)，对I(Ca-L)静息态有阻滞作用。4．关附甲素对I(Ca-L)激活曲线无明显影响，但使I(Ca-L)失活后再激活的恢复时间常数(τ)明显延长，推测可能作用于I(Ca-L)的失活态。
结论：1．因为关附甲素产生明显I(Ca-L)阻滞的浓度远大于临床浓度，其对I(Ca-L)的阻滞作用可能不是抗心律失常的主要作用机制。2．关附甲素呈浓度依赖性阻断I(Ca-L)，关附甲素作用于L型钙通道的静息态，推测可能也作用于失活态。
第二部分：盐酸关附甲素与普罗帕酮对比终止阵发性室上性心动过速的前瞻性随机双盲试验
目的：研究盐酸关附甲素注射液终止阵发性室上性心动过速(PSVT)的疗效及不良事件。比较盐酸关附甲素注射液与普罗帕酮终止PSVT的疗效及不良事件发生率。
方法：随机双盲对照试验。入选标准为18-70岁，体重45-80kg的自发或经食管调搏心房诱发PSVT患者，持续15min以上，心室率＞120次／min者。排除标
Hydrochloric Guanfu base A (GFA) is a new anti-arrhythmic alkaloid with a structure of C20-diterpenoid isolated from the tuber of Aconitum coreanum (Levl.) Raipaics in China. In pre-clinical studies it was shown to slow conduction velocity in nearly all compartments of the heart in vivo and in vitro and exhibited anti-arrhythmic effects in various experimental arrhythmia animal models.
Effects of hydrochloric guanfu base A on heart L-type calcium current in rat ventricular myocytes
OBJECTIVE: The effects of guanfu base A on L-type calcium current (ICa-L) were evaluated under whole-cell recording condition in isolated rat ventricular myocytes. METHODS: Single myocytes were dissociated by enzymatic dissociation method. ICa-L was elicited by depolarization from a holding potential of -50 mV using whole-cell recording techniques.
RESULTS: 1. 25、125、250, 1000μM GFA produced a concentration-dependent reduction of peak L-type calcium current [ ICa-L (pA/pF), at 0mV ] to 81.76%、77.54%、 76.46%、 64.77% from control (P<0.05). 2.GFA upshifted the current-voltage relation (I-V) curves, but the activation voltage, the maximal activation voltage were not significantly altered by GFA. 3.GFA blocked ICa-L in a mild use-dependent manner and GFA exerted a tonic block, which may result from drug interaction with the resting state of the channel. 4. The steady-state activation curve of ICa-L was not significantly affected. 5.GFA significantly delayed the time constant ( τ ) of recovery of ICa-L from inactivation which may suggest that the drug interact with the inactive state of the channel in addition to with resting state.
CONCLUSION: 1.A relatively moderate inhibition of GFA on ICa-L was found, which may not be the principal mechanism of its anti-arrhythmic effect. 2.GFA acts on the resting state and may on the inactivated state of L-type calcium channel.
目的：研究盐酸关附甲素对正常大鼠心室肌细胞L型钙离子通道(I(Ca-L))的影响、旨在探讨其抗心律失常作用机制。
方法：应用经典方法酶解分离大鼠单个心室肌细胞。应用膜片钳全细胞记录方法，维持电位Vh=-50mV，刺激脉冲从-40mV～+50mV诱发出L型钙电流，记录关附甲素对I(Ca-L)的作用并对通道动力学作出初步评价。
结果：1．关附甲素呈浓度依赖性阻断I(Ca-L)，在25、125、250、1000μM时I(Ca-L)峰值电流密度(去极化至0mV时)分别减少为用药前的81.76％、77.54％、76.46％、64.77％，P＜0.05。2．关附甲素使I(Ca-L) Ⅰ-Ⅴ曲线上移，但不改变其激活电位、峰值电位。3．关附甲素呈轻度使用依赖性阻滞I(Ca-L)，对I(Ca-L)静息态有阻滞作用。4．关附甲素对I(Ca-L)激活曲线无明显影响，但使I(Ca-L)失活后再激活的恢复时间常数(τ)明显延长，推测可能作用于I(Ca-L)的失活态。
结论：1．因为关附甲素产生明显I(Ca-L)阻滞的浓度远大于临床浓度，其对I(Ca-L)的阻滞作用可能不是抗心律失常的主要作用机制。2．关附甲素呈浓度依赖性阻断I(Ca-L)，关附甲素作用于L型钙通道的静息态，推测可能也作用于失活态。
第二部分：盐酸关附甲素与普罗帕酮对比终止阵发性室上性心动过速的前瞻性随机双盲试验
目的：研究盐酸关附甲素注射液终止阵发性室上性心动过速(PSVT)的疗效及不良事件。比较盐酸关附甲素注射液与普罗帕酮终止PSVT的疗效及不良事件发生率。
方法：随机双盲对照试验。入选标准为18-70岁，体重45-80kg的自发或经食管调搏心房诱发PSVT患者，持续15min以上，心室率＞120次／min者。排除标
Hydrochloric Guanfu base A (GFA) is a new anti-arrhythmic alkaloid with a structure of C20-diterpenoid isolated from the tuber of Aconitum coreanum (Levl.) Raipaics in China. In pre-clinical studies it was shown to slow conduction velocity in nearly all compartments of the heart in vivo and in vitro and exhibited anti-arrhythmic effects in various experimental arrhythmia animal models.
Effects of hydrochloric guanfu base A on heart L-type calcium current in rat ventricular myocytes
OBJECTIVE: The effects of guanfu base A on L-type calcium current (ICa-L) were evaluated under whole-cell recording condition in isolated rat ventricular myocytes. METHODS: Single myocytes were dissociated by enzymatic dissociation method. ICa-L was elicited by depolarization from a holding potential of -50 mV using whole-cell recording techniques.
RESULTS: 1. 25、125、250, 1000μM GFA produced a concentration-dependent reduction of peak L-type calcium current [ ICa-L (pA/pF), at 0mV ] to 81.76%、77.54%、 76.46%、 64.77% from control (P<0.05). 2.GFA upshifted the current-voltage relation (I-V) curves, but the activation voltage, the maximal activation voltage were not significantly altered by GFA. 3.GFA blocked ICa-L in a mild use-dependent manner and GFA exerted a tonic block, which may result from drug interaction with the resting state of the channel. 4. The steady-state activation curve of ICa-L was not significantly affected. 5.GFA significantly delayed the time constant ( τ ) of recovery of ICa-L from inactivation which may suggest that the drug interact with the inactive state of the channel in addition to with resting state.
CONCLUSION: 1.A relatively moderate inhibition of GFA on ICa-L was found, which may not be the principal mechanism of its anti-arrhythmic effect. 2.GFA acts on the resting state and may on the inactivated state of L-type calcium channel.
引文
1．赵卫红，吴宇澄，王笑云等．耐钙心肌细胞的分离及其L型钙通道电流观察．南京医科大学学报(自然科学版)，2003；23(1)：21-23
2. Hamill, O.P, Marty A, Neher B et al. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, from Appendix of Single Channel Recording
3．裴德安：李庚山；蒋锡嘉等．关附甲素对单个心肌细胞钙通道和内向整流钾通道的阻断作用．中国心脏起搏与心电生理杂志，1999．06．25；13(2)：108-110
4．裴德安．李庚山，蒋锡嘉等．关附甲素对单个心室肌细胞钠通道电流的频率依赖性和使用依赖性阻滞作用．中国心脏起搏与心电生理杂志，1998；12(1)：49～50
5．贾宏钧，王钟林，杨期东主编．离子通道与心脑血管疾病：基础与临床．人民卫生出版社，2001年5月第1版
6．张陆勇．千秋娟，季慧芳等．关附甲素对心肌慢反应动作电位的影响．中国药科大学学报，1994；25(2)：109～112
7．王逸平，陈维洲，顾培堕．关附甲素对离体豚鼠窦房结自发频率的作用．中国药理学报，1990；11(6)：502～505
8. FU Li-Ying1, WANG Fang, Chen Xue-Song2. et al. Perforated patch recording of L-type calcium current with β-escin in guinea pig ventricular myocytes. Acta Pharmacol Sin 2003 Nov; 24 (11):1094-10981. Blomstrom-Lundqvist C, Scheinman MM, Allot EM et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias——executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines. at http://www.acc.org
2. Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med, 1991, 325:1621-1629.
3. Wilbur SL, Marchlinski FE. Adenosine as an antiarrhythmic agent. Am J Cardiol, 1997, 79(12A) :30237.
4．国产腺苷与维拉帕米终止室上性心动过速试验组．国产腺苷和维拉帕米终止室上性心动过速的临床研究．中华内科杂志，2003；42(11)
5. Kuhn M. Verapamil in the treatment of PSVT. Ann Emerg Med ,1981,10:538-544.
6. Rae AP. Placebo-controlled evaluations of propafenone for atrial tachyarrhythmias. Am J Cardiol. 1998 Oct 16;82(8A):59N-65N
7．临床心血管病杂志1998年14卷2期105
8．吴辉清、王少彬、陈宋章．静脉注射普罗帕酮治疗阵发性室上性心动过速82例临床体会．广州医药，1997；28(3)
9．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志，2001．02．28；29(2)：124
10. Prodird PT. Propafenone noninvasive evaluation of efficacy. Am J Cardiol, 1984,54:530
11．张澍．静脉注射心律平的电生理效应观察．中华心血管病杂志，1989，17(3)：1331. Braunwald. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed., 2001 W. B. Saunders Company
2. Mohiuddin S, Hilleman D, Mooss Aryan et al. Double-blind randomized comparison of intravenous tocainide versus lidocaine in the treatment of chronic ventricular arrhythmias. Am Heart J 1987;114:296
3. Shen E, Sung R, Morady F et al Electrophysiologic and hemodynamic effects of intravenous propafenone in patients with recurrent ventricular tachycardia J Am Coil Cardiol 1984 ;3 (5):1291-7
4. Hemandez M, Reder R, Marinchak R et al. Propafenone for malignant ventricular arrhythrnia: An analysis of the literature Am Heart J 1991;121(4)1178-1184
5．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志．2001．02．28；29(2)：124
6．裴德安，蒋锡嘉，李庚山等．关附甲素对单个心肌细胞钠通道的阻断作用．心脏起搏与心脏电生理杂志，1995；9(4)：207-209
7．张陆勇，季慧芳，王秋娟等．关附甲素对心肌细胞电生理特性的影响．中国药科大学学报，1991；22(6)：354～358
8．周礼明，徐济民，陈祥华等．关附甲素对豚鼠，心室乳头状肌细胞动作电位的电生理效应．中国药理学报，1991；12(5)：465～467
9. Hodges M, Salerno D, Granrud G. Double-blind placebo-controlled evaluation of propafenone in suppressing ventricular ectopic activity. Am J Cardiol 1984;54:45D-50D1．韩英，刘静涵，王明时．黄花乌头植物化学成分的研究．中草药，1994；25(12)：619-624
2．张陆勇，王秋娟，季慧芳等．关附甲素对心肌慢反应动作电位的影响．中国药科大学学报，1994；25(2)：109～112
3．王逸平，陈维洲，顾培堕．关附甲素对离体豚鼠窦房结自发频率的作用．中国药理学报，1990：11(6)：502～505
4．后德辉，李玲，王秋娟等．关附甲素对实验性心律失常的作用．南京药学院学报，1981；2：68-71
5．陈维洲，董月丽，张月芳等．关附甲素的抗心律失常作用．中国药理学报，1983：4(4)：247～250
6．陈祥华，徐济民，周礼明等．关附甲素对麻醉兔心脏传导和收缩的影响．上海第二医科大学学报，1992；(2)：93-97
7．王友群，苏玲，龚国清等．关附甲素抑制犬冠脉结扎引起的心律失常．药学学报，1994；29(2)：141～144
8．张陆勇，季慧芳，王秋娟等．关附甲素对心肌细胞电生理特性的影响．中国药科大学学报，1991；22(6)：354～358
9．周礼明，徐济民，陈祥华等．关附甲素对豚鼠心室乳头状肌细胞动作电位的电生理效应．中国药理学报，1991；12(5)：465～467
10．陈红专，顾培埅，章鲁等．关附甲素对豚鼠乳头肌快反应动作电位的作用．中国药理学报，1989；10(5)：399～401
11．陈红专，顾培壁，章鲁等．卢关附中素对北草乌头碱引起豚鼠心肌自发节律的影响．上海第二医科大学学报，1989；9(2)：105～108
12．章鲁，顾培埅，赵文宝等．关附甲素对犬心浦肯野氏纤维动作电位的作用．中国药理学报，1986；7(3)：234～236
13．裴德安，蒋锡嘉，李庚山等．关附甲素对单个心肌细胞钠通道的阻断作用．心脏起搏与心脏电生理杂志，1995；9(4)：207～209
14．裴德安，李庚山，蒋锡嘉等．关附甲素对单个心室肌细胞钠通道电流的频率依赖性和使刚依赖性阻滞作用．中国心脏起搏与心电生理杂志，1998；12(1)：49～50
15．裴德安：李庚山；蒋锡嘉等．关附甲素对单个心肌细胞钙通道和内向整流钾通道的阻断作用．中国心脏起搏与心电生理杂志，1999．06．25；13(2)：108-110
16．王逸平，陈维洲，王晓良等．关附甲素对豚鼠心室肌细胞延迟整流钾电流的抑制作用．药学学报，1996；31(8)：581～584
17．张陆勇，季慧芳，王秋娟等．关附甲素对豚鼠左心房肌的变力性作用．中国药科大学学报，1994；25(3)：170～172
18．董月丽，陈维洲．关附甲素对实验性心律失常和心肌收缩性的影响．药学学报，1995．08．28；30(8)：577-582
19．陈维洲，董月丽，张月芳等．关附甲素的抗心律失常作用．中国药理学报，1983：4(4)：247～250
20．王秋娟，张陆勇，唐名月等．盐酸关附甲素注射液对实验性心律失常的作用．现代应用药学，1996；13(4)：7～9
21．王友群，苏玲，龚国清等．关附甲素抑制犬冠脉结扎引起的心律失常．药学学报，1994；29(2)：141～144
22．王国干，崔华东，朱俊等．静脉注射盐酸关附甲素的人体药代动力学研究．中国临床药理学杂志，2000．07．28；16(4)：283-285
23．阿基业，王广基，柳晓泉等．高效液相-质谱联用法对盐酸关附甲素在大鼠尿中代谢物的研究．药学学报，2002．04．12；37(4)：283-287
24．阿基业．中国药科大学博士论文25．杨艳敏，康连鸣，朱俊等．盐酸关附甲素注射液Ⅰ期耐受性试验研究．中国心脏起搏与心电生理杂志，2001．08．25；1 5(41：258-260
26．朱俊，杨艳敏，李萍等．盐酸关附甲素注射液血流动力学作用研究．中国临床药理学杂志，2000．11．28；16(6)：412-414
27．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志，2001．02．28；29(2)：124
28．王智勇，郭继鸿，许原．盐酸关附甲素终止阵发性室上性心动过速的临床研究．中国实用内科杂志，2002．04．10；22(4)：212-213
29．韩智红，吴学思，朱晓玲等．盐酸关附甲素注射液终止室上性心动过速的疗效．中国新药杂志，2003．12(11)：939-940
30．冯赫林，张帆，张镇钟等．盐酸关附甲素治疗室性心律失常疗效的临床研究．医学临床研究，2002．10．26；19(5)：331-333
31．韩智红，吴学思，贾世杰等．盐酸关附甲素注射液对室性早搏的疗效与安全性观察．心肺血管病杂志，2003．08．27；22(3)：144-1461. Nilius B, Hess P, Lansman JB, Tsien RW: A novel type of cardiac calcium channel in ventricular cells. Nature 316: 443-446, 1985.
2. Marban E, Robinson SW, Wier WG: Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 78: 1185-1192, 1986.
3. January CT, Riddle JM: Early afterdepolarizations: Mechanism of induction and block. A role for L-type Ca~(2+) current. Circ Res 64: 977-990, 1989.
4. Ringer S: A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol 4: 29-42, 1883.
5. Schultz D,Midala jG, Yatani A,et al. Cloning,chromosomal localizationand functional expressionof the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci USA,1993, 90: 10494
6. Iles DE,Lehmann-Horn F,Scherer,SW, et al. Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. HumMol Genet, 1994, 3: 969
7. Colin T,Wang JJ,Nargeot J,et al. molecular cloning of three isofroms ofthe L-type voltage-dependent calcium channel beta subunit from normalhuman heart. Circ Res, 1993, 72: 1337
8. Morillo CA,Klein GJ,Jones DL,et al. Chronic rapid atrial pacing:structural,functional,and electrophysiological characteristics of a new modelof sustained atrial fibrillation. Circulation,1995, 91: 1588
9. Goette A,Honeycutt C,Langberg JJ. Electrical remodeling in atrial fibrillation:time course and mechanisms. Circulation,1996, 94: 2968
10. Catterall WA: Structure and function of voltage-sensitive ion channels. Science 242: 50-61, 1988.
11. Noda M, Shimizu S, Tanabe T, et al: Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312: 121-127, 1984.
12. Stuhmer W, Conti F, Suzuki H, et al: Structural parts involved in activation and inactivation of the sodium channel. Nature 339: 597-603, 1989.
13. Tomaselli GF, Backx PH, Marban E: Permeation in voltage-gated ion channels. Circ Res 72: 491-496, 1993.
14. Miller C: 1990: Annus mirabilis of potassium channels. Science 252: 1092-1096, 1991.
15. Backx PH, Yue DT, Lawrence JH, et al: Molecular localization of an ion-binding site within the pore of mammalian sodium channels. Science 257: 248-251, 1992.
16. Yue DT, Marban E: Permeation in the dihydropyridine-sensitive calcium channel: Multi-ion occupancy but no anomalous mole-fraction effect between Ba~(2+) and Ca~(2+). J Gen Physiol 95: 911-939, 1990.
17. Hess P, Tsien RW: Mechanism of ion permeation through calcium channels. Nature 309: 453-456, 1984.
18. Hadley RW, Hume JR: An intrinsic potential-dependent inactivation mechanism associated with calcium channels in guinea-pig myocytes. J Physiol 389: 205-222, 1987.
19. Heinemann SH, Terlau H, Stuhmer W, et al: Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356: 441-443, 1992.
20. Kim M-S, Morii T, Sun L-X, et al: Structural determinants of ion selectivity in brain calcium channel. FEBS Lett 318: 145-148, 1993.
21. Tang S, Mikala G, Bahinski A, et al: Molecular localization of ion selectivity sites within the pore of a human cardiac L-type calcium channel. J Biol Chem 286:13026-13029, 1993.
22. Yang J, Ellinor PT, Sather WA, et al: Molecular determinants of Ca selectivity and ion permeation in L-type Ca channels. Nature 366:158-161, 1993.
23. Winegar B, Lansman JB: Voltage-dependent block by zinc of single calcium channels in mouse myotubes. J Physiol 425:563-578, 1990.
24. Lansman JB: Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit. J Gen Physiol 95:679-696, 1990.
25. Mikami A, Imoro K, Tanabe T, et al: Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature 340:230-233, 1989.
26. Perez-Reyes E, Kim HS, Lacerda AE, et al: Induction of calcium currents by the expression of the alpha_1 subunit of the dihydropyridine receptor from skeletal muscle. Nature 340:233-236, 1989.
27. Tanabe T, Beam KG, Adams BA, et al: Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature 346:567-572, 1990.
28. Tanabe T, Adams BA, Numa S, Beam KG: Repeat I of the dihydropyridine receptor is critical in determining calcium channel activation kinetics. Nature 352:800-803, 1991.
29．贾宏钧，王钟林，杨期东主编．离子通道与心脑血管疾病：基础与临床．人民卫生出版社，2001年5月第1版
30. Qu Y, Boutjdir M. Gene expression of SERCA2a and L- and T-type Ca channels during human heart development. Pediatr Res, 2001,50 (5) : 569-574.
31. Wang YQ, Brooks G, Zhu CB, et al. Functional analysis of the human T-type calcium channel a 1H subunit gene in cellular proliferation. Yi Chuan Xue Bao, 2002,29 (8) : 659-665.
32. Scoote M, Williams AJ. The cardiac ryanodine receptor (calcium release channel) : Emerging role in heart failure and arrhythmia pathogenesis. Cardiovasc Research, 2002,56:359
33. Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature, 1992 ;355 (6358) :353～6
34. Donald M. Bers Cardiac excitation-contraction coupling Nature 10 JAN 2002 VOL 415:198-205
35. Xin H, Senboumatsu T, Cheng D, et al. Oestrogen protects FKBP 12.6 null mice from cardiac hypertrophy. Nature 2002;416:334-7.
36. Ono K, Yano M, Ohkusa T, et al. Altered interaction of FKBP 12.6 with ryanodine receptor as a cause of abnormal calcium release in heart failure. Cardiovasc Res 2000;48:323-31.
37. Gorza L, Schiaffino S, Volpe P: Inositol 1,4,5-trisphosphate receptor in heart: Evidence for its concentration in Purkinje myocytes of the conduction system. J Cell Biol 121:345-353, 1993.
38. Kijima Y, Saito A, Jetton TL, et al: Different intracellular localization of inositol 1,4,5-trisphosphate and ryanodine receptors in cardiomyoeytes. J Biol Chem 268:3499-3506, 1993.
39. Aggarwal R, Shorofsky SR, Goldman L, Balke CW: Tetrodotoxin-blockable calcium currents in rat ventficular myocytes: A third type of cardiac cell sodium current. J Physiol 505:353-369, 1997.
40. Shinichi Hatta·Jun Sakamoto · Yoshiyuki Horio Ion channels and diseases Med Electron Microsc (2002) 35:117-126
41. Richardson P,Mckenna W, Bristow M. Report of the 1995 World Health Organization/ International Society and Federation of Cardiomyopathies. Circulation ,1996,93 (2) :841-842.
42. Mckenna WJ ,Thiene G, Nava A ,et al. Diagnosis of arrhythmogenic fight ventriular dysplasia/cardiomyopathy. Br Heart J, 1994,71 (3) : 215 -218.
43. Rampazzo A, Nava A, Buja G, et al. The gene for arrythmogenic right ventricular cardiomypathy??maps to chromosome 14q232q24.Hum Mol Genet, 1994, 3: 959-962.
44. Rampazzo A, Nava A, Erne P, et al. A new locus for arrythmogenic right ventricular cardiomypathy (ARVC2) maps to chromosome 1q422q43. Hum Mol Genet, 1995, 4: 2151-2154.
45. Severini GM, Krajinovic M, Pinamonti B, et al. A new locus for arrythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics, 1996, 31: 193-200.
46. Rampazzo A, Nava A, Miorin M, et al. ARVC4: a new locus for arrythmogenic right ventricular cardiomypath, maps to chromosome-long arm. Genomics, 1997, 45: 259-263.
47. Ahmad F, Li Duanxiang, Karibe A, et al. Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23. Circulation, 1998, 98: 2791-2795.
48. Li Duanxiang, Ahmad F, Gardner MJ, et al. The locus of a novel gene responsible for arrhythmogenic right ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p122p14. Am J Hum Genet, 2000, 66: 148-156.
49. Melberg A, Oldfors A, Blomstrom2Lundqvist C, et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol, 1999, 46: 684-692.
50. Coonar AS, Protonotarios N, Tsatsopoulou A, et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation, 1998, 97: 2049-2058.
51. Tiso N, Stephan D, Nava A, et al. Identification of mutations inthe cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).Hum Mol Genet, 2001, 10: 189
52. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995; 91: 1512-9.
53. Swan H, Piippo K, Viitasalo M et al Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999; 34: 2035-42
54. Priori S, Napolitano C, Tiso N. Mutations in the cardiac ryanodine receptor gene underlie catecholaminergic polymorphic ventricular tachycardia. Circulation, 2000, 102: 49
55. Laitinen P, Brown K, Piippo K, et al. Mutations of the cardiac ryanodine receptor gene in familial polymorphic ventricular tachycardia. Circulation, 2001, 103: 4 485
56. Lahat H, Pras E, Olender T, et al. Missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine2induced polymorphic ventricular tachycardia in Bedouin families from Israel. AmJ Hum Genet, 2001, 69: 1 378
57. Sagawa T, Sagawa K, Kelly J, et al. Activation of cardiac ryanodine receptors by cardiac glycosides. Am J Physiol Heart Circ Physiol, 2002, 282: H1 118
58. Nakajima T, Kaneko Y, Taniguchi Y, et al. The mechanism of catecholaminergic polymorphic ventricular tachycardia may be triggered activity due to delayed afterdepolarizations. Eur Heart J, 1997, 18: 530
59. Jiang D, Xiao B, Zhang L, et al. Enhanced basal activity of a cardiac calcium release channel mutant associated with ventricular tachycardia and sudden death. Circ Res, 2002, 91: 218
60. Christopher H. George, Gemma V. Higgs, F et al Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes Circ Res. 2003; 93: 531-540
61. Wehrens X, Lehmart S, Huang F et al FKBP 12.6 deficiency and defective calcium release channel(ryanodine receptor) function linked to exercise-induced sudden cardiac death Cell 2003; 113: 829-840
62. Schafers M, Lerch H, Wichter T et al Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 1998; 32: 181-186
63. Lerman BB, Dong B, Stein KM et al Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunit α i2. J Clin Invest 1998; 101: 2862-8
2. Hamill, O.P, Marty A, Neher B et al. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, from Appendix of Single Channel Recording
3．裴德安：李庚山；蒋锡嘉等．关附甲素对单个心肌细胞钙通道和内向整流钾通道的阻断作用．中国心脏起搏与心电生理杂志，1999．06．25；13(2)：108-110
4．裴德安．李庚山，蒋锡嘉等．关附甲素对单个心室肌细胞钠通道电流的频率依赖性和使用依赖性阻滞作用．中国心脏起搏与心电生理杂志，1998；12(1)：49～50
5．贾宏钧，王钟林，杨期东主编．离子通道与心脑血管疾病：基础与临床．人民卫生出版社，2001年5月第1版
6．张陆勇．千秋娟，季慧芳等．关附甲素对心肌慢反应动作电位的影响．中国药科大学学报，1994；25(2)：109～112
7．王逸平，陈维洲，顾培堕．关附甲素对离体豚鼠窦房结自发频率的作用．中国药理学报，1990；11(6)：502～505
8. FU Li-Ying1, WANG Fang, Chen Xue-Song2. et al. Perforated patch recording of L-type calcium current with β-escin in guinea pig ventricular myocytes. Acta Pharmacol Sin 2003 Nov; 24 (11):1094-10981. Blomstrom-Lundqvist C, Scheinman MM, Allot EM et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias——executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the European Society of Cardiology Committee for Practice Guidelines. at http://www.acc.org
2. Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med, 1991, 325:1621-1629.
3. Wilbur SL, Marchlinski FE. Adenosine as an antiarrhythmic agent. Am J Cardiol, 1997, 79(12A) :30237.
4．国产腺苷与维拉帕米终止室上性心动过速试验组．国产腺苷和维拉帕米终止室上性心动过速的临床研究．中华内科杂志，2003；42(11)
5. Kuhn M. Verapamil in the treatment of PSVT. Ann Emerg Med ,1981,10:538-544.
6. Rae AP. Placebo-controlled evaluations of propafenone for atrial tachyarrhythmias. Am J Cardiol. 1998 Oct 16;82(8A):59N-65N
7．临床心血管病杂志1998年14卷2期105
8．吴辉清、王少彬、陈宋章．静脉注射普罗帕酮治疗阵发性室上性心动过速82例临床体会．广州医药，1997；28(3)
9．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志，2001．02．28；29(2)：124
10. Prodird PT. Propafenone noninvasive evaluation of efficacy. Am J Cardiol, 1984,54:530
11．张澍．静脉注射心律平的电生理效应观察．中华心血管病杂志，1989，17(3)：1331. Braunwald. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed., 2001 W. B. Saunders Company
2. Mohiuddin S, Hilleman D, Mooss Aryan et al. Double-blind randomized comparison of intravenous tocainide versus lidocaine in the treatment of chronic ventricular arrhythmias. Am Heart J 1987;114:296
3. Shen E, Sung R, Morady F et al Electrophysiologic and hemodynamic effects of intravenous propafenone in patients with recurrent ventricular tachycardia J Am Coil Cardiol 1984 ;3 (5):1291-7
4. Hemandez M, Reder R, Marinchak R et al. Propafenone for malignant ventricular arrhythrnia: An analysis of the literature Am Heart J 1991;121(4)1178-1184
5．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志．2001．02．28；29(2)：124
6．裴德安，蒋锡嘉，李庚山等．关附甲素对单个心肌细胞钠通道的阻断作用．心脏起搏与心脏电生理杂志，1995；9(4)：207-209
7．张陆勇，季慧芳，王秋娟等．关附甲素对心肌细胞电生理特性的影响．中国药科大学学报，1991；22(6)：354～358
8．周礼明，徐济民，陈祥华等．关附甲素对豚鼠，心室乳头状肌细胞动作电位的电生理效应．中国药理学报，1991；12(5)：465～467
9. Hodges M, Salerno D, Granrud G. Double-blind placebo-controlled evaluation of propafenone in suppressing ventricular ectopic activity. Am J Cardiol 1984;54:45D-50D1．韩英，刘静涵，王明时．黄花乌头植物化学成分的研究．中草药，1994；25(12)：619-624
2．张陆勇，王秋娟，季慧芳等．关附甲素对心肌慢反应动作电位的影响．中国药科大学学报，1994；25(2)：109～112
3．王逸平，陈维洲，顾培堕．关附甲素对离体豚鼠窦房结自发频率的作用．中国药理学报，1990：11(6)：502～505
4．后德辉，李玲，王秋娟等．关附甲素对实验性心律失常的作用．南京药学院学报，1981；2：68-71
5．陈维洲，董月丽，张月芳等．关附甲素的抗心律失常作用．中国药理学报，1983：4(4)：247～250
6．陈祥华，徐济民，周礼明等．关附甲素对麻醉兔心脏传导和收缩的影响．上海第二医科大学学报，1992；(2)：93-97
7．王友群，苏玲，龚国清等．关附甲素抑制犬冠脉结扎引起的心律失常．药学学报，1994；29(2)：141～144
8．张陆勇，季慧芳，王秋娟等．关附甲素对心肌细胞电生理特性的影响．中国药科大学学报，1991；22(6)：354～358
9．周礼明，徐济民，陈祥华等．关附甲素对豚鼠心室乳头状肌细胞动作电位的电生理效应．中国药理学报，1991；12(5)：465～467
10．陈红专，顾培埅，章鲁等．关附甲素对豚鼠乳头肌快反应动作电位的作用．中国药理学报，1989；10(5)：399～401
11．陈红专，顾培壁，章鲁等．卢关附中素对北草乌头碱引起豚鼠心肌自发节律的影响．上海第二医科大学学报，1989；9(2)：105～108
12．章鲁，顾培埅，赵文宝等．关附甲素对犬心浦肯野氏纤维动作电位的作用．中国药理学报，1986；7(3)：234～236
13．裴德安，蒋锡嘉，李庚山等．关附甲素对单个心肌细胞钠通道的阻断作用．心脏起搏与心脏电生理杂志，1995；9(4)：207～209
14．裴德安，李庚山，蒋锡嘉等．关附甲素对单个心室肌细胞钠通道电流的频率依赖性和使刚依赖性阻滞作用．中国心脏起搏与心电生理杂志，1998；12(1)：49～50
15．裴德安：李庚山；蒋锡嘉等．关附甲素对单个心肌细胞钙通道和内向整流钾通道的阻断作用．中国心脏起搏与心电生理杂志，1999．06．25；13(2)：108-110
16．王逸平，陈维洲，王晓良等．关附甲素对豚鼠心室肌细胞延迟整流钾电流的抑制作用．药学学报，1996；31(8)：581～584
17．张陆勇，季慧芳，王秋娟等．关附甲素对豚鼠左心房肌的变力性作用．中国药科大学学报，1994；25(3)：170～172
18．董月丽，陈维洲．关附甲素对实验性心律失常和心肌收缩性的影响．药学学报，1995．08．28；30(8)：577-582
19．陈维洲，董月丽，张月芳等．关附甲素的抗心律失常作用．中国药理学报，1983：4(4)：247～250
20．王秋娟，张陆勇，唐名月等．盐酸关附甲素注射液对实验性心律失常的作用．现代应用药学，1996；13(4)：7～9
21．王友群，苏玲，龚国清等．关附甲素抑制犬冠脉结扎引起的心律失常．药学学报，1994；29(2)：141～144
22．王国干，崔华东，朱俊等．静脉注射盐酸关附甲素的人体药代动力学研究．中国临床药理学杂志，2000．07．28；16(4)：283-285
23．阿基业，王广基，柳晓泉等．高效液相-质谱联用法对盐酸关附甲素在大鼠尿中代谢物的研究．药学学报，2002．04．12；37(4)：283-287
24．阿基业．中国药科大学博士论文25．杨艳敏，康连鸣，朱俊等．盐酸关附甲素注射液Ⅰ期耐受性试验研究．中国心脏起搏与心电生理杂志，2001．08．25；1 5(41：258-260
26．朱俊，杨艳敏，李萍等．盐酸关附甲素注射液血流动力学作用研究．中国临床药理学杂志，2000．11．28；16(6)：412-414
27．朱俊，李萍，杨艳敏等．盐酸关附甲素注射液的人体电生理作用．中华心血管病杂志，2001．02．28；29(2)：124
28．王智勇，郭继鸿，许原．盐酸关附甲素终止阵发性室上性心动过速的临床研究．中国实用内科杂志，2002．04．10；22(4)：212-213
29．韩智红，吴学思，朱晓玲等．盐酸关附甲素注射液终止室上性心动过速的疗效．中国新药杂志，2003．12(11)：939-940
30．冯赫林，张帆，张镇钟等．盐酸关附甲素治疗室性心律失常疗效的临床研究．医学临床研究，2002．10．26；19(5)：331-333
31．韩智红，吴学思，贾世杰等．盐酸关附甲素注射液对室性早搏的疗效与安全性观察．心肺血管病杂志，2003．08．27；22(3)：144-1461. Nilius B, Hess P, Lansman JB, Tsien RW: A novel type of cardiac calcium channel in ventricular cells. Nature 316: 443-446, 1985.
2. Marban E, Robinson SW, Wier WG: Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 78: 1185-1192, 1986.
3. January CT, Riddle JM: Early afterdepolarizations: Mechanism of induction and block. A role for L-type Ca~(2+) current. Circ Res 64: 977-990, 1989.
4. Ringer S: A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol 4: 29-42, 1883.
5. Schultz D,Midala jG, Yatani A,et al. Cloning,chromosomal localizationand functional expressionof the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci USA,1993, 90: 10494
6. Iles DE,Lehmann-Horn F,Scherer,SW, et al. Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. HumMol Genet, 1994, 3: 969
7. Colin T,Wang JJ,Nargeot J,et al. molecular cloning of three isofroms ofthe L-type voltage-dependent calcium channel beta subunit from normalhuman heart. Circ Res, 1993, 72: 1337
8. Morillo CA,Klein GJ,Jones DL,et al. Chronic rapid atrial pacing:structural,functional,and electrophysiological characteristics of a new modelof sustained atrial fibrillation. Circulation,1995, 91: 1588
9. Goette A,Honeycutt C,Langberg JJ. Electrical remodeling in atrial fibrillation:time course and mechanisms. Circulation,1996, 94: 2968
10. Catterall WA: Structure and function of voltage-sensitive ion channels. Science 242: 50-61, 1988.
11. Noda M, Shimizu S, Tanabe T, et al: Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312: 121-127, 1984.
12. Stuhmer W, Conti F, Suzuki H, et al: Structural parts involved in activation and inactivation of the sodium channel. Nature 339: 597-603, 1989.
13. Tomaselli GF, Backx PH, Marban E: Permeation in voltage-gated ion channels. Circ Res 72: 491-496, 1993.
14. Miller C: 1990: Annus mirabilis of potassium channels. Science 252: 1092-1096, 1991.
15. Backx PH, Yue DT, Lawrence JH, et al: Molecular localization of an ion-binding site within the pore of mammalian sodium channels. Science 257: 248-251, 1992.
16. Yue DT, Marban E: Permeation in the dihydropyridine-sensitive calcium channel: Multi-ion occupancy but no anomalous mole-fraction effect between Ba~(2+) and Ca~(2+). J Gen Physiol 95: 911-939, 1990.
17. Hess P, Tsien RW: Mechanism of ion permeation through calcium channels. Nature 309: 453-456, 1984.
18. Hadley RW, Hume JR: An intrinsic potential-dependent inactivation mechanism associated with calcium channels in guinea-pig myocytes. J Physiol 389: 205-222, 1987.
19. Heinemann SH, Terlau H, Stuhmer W, et al: Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356: 441-443, 1992.
20. Kim M-S, Morii T, Sun L-X, et al: Structural determinants of ion selectivity in brain calcium channel. FEBS Lett 318: 145-148, 1993.
21. Tang S, Mikala G, Bahinski A, et al: Molecular localization of ion selectivity sites within the pore of a human cardiac L-type calcium channel. J Biol Chem 286:13026-13029, 1993.
22. Yang J, Ellinor PT, Sather WA, et al: Molecular determinants of Ca selectivity and ion permeation in L-type Ca channels. Nature 366:158-161, 1993.
23. Winegar B, Lansman JB: Voltage-dependent block by zinc of single calcium channels in mouse myotubes. J Physiol 425:563-578, 1990.
24. Lansman JB: Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit. J Gen Physiol 95:679-696, 1990.
25. Mikami A, Imoro K, Tanabe T, et al: Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature 340:230-233, 1989.
26. Perez-Reyes E, Kim HS, Lacerda AE, et al: Induction of calcium currents by the expression of the alpha_1 subunit of the dihydropyridine receptor from skeletal muscle. Nature 340:233-236, 1989.
27. Tanabe T, Beam KG, Adams BA, et al: Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature 346:567-572, 1990.
28. Tanabe T, Adams BA, Numa S, Beam KG: Repeat I of the dihydropyridine receptor is critical in determining calcium channel activation kinetics. Nature 352:800-803, 1991.
29．贾宏钧，王钟林，杨期东主编．离子通道与心脑血管疾病：基础与临床．人民卫生出版社，2001年5月第1版
30. Qu Y, Boutjdir M. Gene expression of SERCA2a and L- and T-type Ca channels during human heart development. Pediatr Res, 2001,50 (5) : 569-574.
31. Wang YQ, Brooks G, Zhu CB, et al. Functional analysis of the human T-type calcium channel a 1H subunit gene in cellular proliferation. Yi Chuan Xue Bao, 2002,29 (8) : 659-665.
32. Scoote M, Williams AJ. The cardiac ryanodine receptor (calcium release channel) : Emerging role in heart failure and arrhythmia pathogenesis. Cardiovasc Research, 2002,56:359
33. Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature, 1992 ;355 (6358) :353～6
34. Donald M. Bers Cardiac excitation-contraction coupling Nature 10 JAN 2002 VOL 415:198-205
35. Xin H, Senboumatsu T, Cheng D, et al. Oestrogen protects FKBP 12.6 null mice from cardiac hypertrophy. Nature 2002;416:334-7.
36. Ono K, Yano M, Ohkusa T, et al. Altered interaction of FKBP 12.6 with ryanodine receptor as a cause of abnormal calcium release in heart failure. Cardiovasc Res 2000;48:323-31.
37. Gorza L, Schiaffino S, Volpe P: Inositol 1,4,5-trisphosphate receptor in heart: Evidence for its concentration in Purkinje myocytes of the conduction system. J Cell Biol 121:345-353, 1993.
38. Kijima Y, Saito A, Jetton TL, et al: Different intracellular localization of inositol 1,4,5-trisphosphate and ryanodine receptors in cardiomyoeytes. J Biol Chem 268:3499-3506, 1993.
39. Aggarwal R, Shorofsky SR, Goldman L, Balke CW: Tetrodotoxin-blockable calcium currents in rat ventficular myocytes: A third type of cardiac cell sodium current. J Physiol 505:353-369, 1997.
40. Shinichi Hatta·Jun Sakamoto · Yoshiyuki Horio Ion channels and diseases Med Electron Microsc (2002) 35:117-126
41. Richardson P,Mckenna W, Bristow M. Report of the 1995 World Health Organization/ International Society and Federation of Cardiomyopathies. Circulation ,1996,93 (2) :841-842.
42. Mckenna WJ ,Thiene G, Nava A ,et al. Diagnosis of arrhythmogenic fight ventriular dysplasia/cardiomyopathy. Br Heart J, 1994,71 (3) : 215 -218.
43. Rampazzo A, Nava A, Buja G, et al. The gene for arrythmogenic right ventricular cardiomypathy??maps to chromosome 14q232q24.Hum Mol Genet, 1994, 3: 959-962.
44. Rampazzo A, Nava A, Erne P, et al. A new locus for arrythmogenic right ventricular cardiomypathy (ARVC2) maps to chromosome 1q422q43. Hum Mol Genet, 1995, 4: 2151-2154.
45. Severini GM, Krajinovic M, Pinamonti B, et al. A new locus for arrythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics, 1996, 31: 193-200.
46. Rampazzo A, Nava A, Miorin M, et al. ARVC4: a new locus for arrythmogenic right ventricular cardiomypath, maps to chromosome-long arm. Genomics, 1997, 45: 259-263.
47. Ahmad F, Li Duanxiang, Karibe A, et al. Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23. Circulation, 1998, 98: 2791-2795.
48. Li Duanxiang, Ahmad F, Gardner MJ, et al. The locus of a novel gene responsible for arrhythmogenic right ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p122p14. Am J Hum Genet, 2000, 66: 148-156.
49. Melberg A, Oldfors A, Blomstrom2Lundqvist C, et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol, 1999, 46: 684-692.
50. Coonar AS, Protonotarios N, Tsatsopoulou A, et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation, 1998, 97: 2049-2058.
51. Tiso N, Stephan D, Nava A, et al. Identification of mutations inthe cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).Hum Mol Genet, 2001, 10: 189
52. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995; 91: 1512-9.
53. Swan H, Piippo K, Viitasalo M et al Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999; 34: 2035-42
54. Priori S, Napolitano C, Tiso N. Mutations in the cardiac ryanodine receptor gene underlie catecholaminergic polymorphic ventricular tachycardia. Circulation, 2000, 102: 49
55. Laitinen P, Brown K, Piippo K, et al. Mutations of the cardiac ryanodine receptor gene in familial polymorphic ventricular tachycardia. Circulation, 2001, 103: 4 485
56. Lahat H, Pras E, Olender T, et al. Missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine2induced polymorphic ventricular tachycardia in Bedouin families from Israel. AmJ Hum Genet, 2001, 69: 1 378
57. Sagawa T, Sagawa K, Kelly J, et al. Activation of cardiac ryanodine receptors by cardiac glycosides. Am J Physiol Heart Circ Physiol, 2002, 282: H1 118
58. Nakajima T, Kaneko Y, Taniguchi Y, et al. The mechanism of catecholaminergic polymorphic ventricular tachycardia may be triggered activity due to delayed afterdepolarizations. Eur Heart J, 1997, 18: 530
59. Jiang D, Xiao B, Zhang L, et al. Enhanced basal activity of a cardiac calcium release channel mutant associated with ventricular tachycardia and sudden death. Circ Res, 2002, 91: 218
60. Christopher H. George, Gemma V. Higgs, F et al Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes Circ Res. 2003; 93: 531-540
61. Wehrens X, Lehmart S, Huang F et al FKBP 12.6 deficiency and defective calcium release channel(ryanodine receptor) function linked to exercise-induced sudden cardiac death Cell 2003; 113: 829-840
62. Schafers M, Lerch H, Wichter T et al Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 1998; 32: 181-186
63. Lerman BB, Dong B, Stein KM et al Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunit α i2. J Clin Invest 1998; 101: 2862-8