钠钙交换体及其抑制剂在心律失常中的作用

摘要/Abstract

摘要： 在心肌细胞中, 钠钙交换体对胞内钙离子的调控起着非常重要的作用。缺血再灌注或强心苷中毒时会使细胞外的钙通过钠钙交换体的反向模式内流, 造成内钙超载, 导致心律失常。现今, 选择性抑制其反向模式的苄氧基苯基衍生物得到了较多的研究, 并可能成为治疗心律失常的一个新的有潜力靶点。

关键词: 钠钙交换体, 反向模式, 钙超载, 钠钙交换体抑制剂, 心律失常

Abstract: In cardiomyocytes, sodium-calcium exchanger (NCX) is regarded to play an important role in the regulation of intracellular Ca²⁺concentration.During the cardiac ischemia reperfusion or cardenolide intoxication, the inflow Ca²⁺through NCX reverse mode induce calcium overload and arrhythmia.Recently, the benzyloxyphenyl derivatives have been developed as selective NCX inhibitors, which may have therapeutic potential as a new remedy for arrhythmias.

Key words: sodium-calcium exchanger, reverse mode, calcium overload, sodium-calcium exchanger inhibitor, arrhythmia

中图分类号:

R541.7
R962

沈磊, 吴玉林. 钠钙交换体及其抑制剂在心律失常中的作用[J]. 中国临床药理学与治疗学, 2006, 11(6): 610-613.

SHEN Lei, WU Yu-lin. Effect of sodium-calcium exchanger and its inhibitors on arrhythmia[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(6): 610-613.

参考文献

1 Blaustein MP, Lederer WJ.Sodium calcium exchange:its physiological implications[J].Physiol Rev, 1999;79:763-854
2 Iwamoto T.Forefront of Na⁺ Ca²⁺exchanger studies:molecular pharmacology of Na⁺ Ca²⁺ exchange inhibitors[J].J Pharmacol Sci, 2004;96:27-32
3 Hobai IA, O'Rourke B.The potential of Na⁺ Ca²⁺Exchange blockers in the treatment of cardiac disease[J].Expert Opin Investig Drugs, 2004;13:653-64
4 Iwamoto T, Kita S, Uehara A, Imanaga I, Matsuda T, Baba A, et al.Molecular Determinants of Na⁺ Ca²⁺Exchange (NCX1) Inhibition by SEA0400[J].J Biol Chem, 2004;279: 7544-53
5 Hannes Reuter, Scott A.Henderson, Tieyan Han, Giuliano A, Joy S Frank, et al.Cardiac excitation-contraction coupling in the absence of Na⁺-Ca²⁺exchange[J].Cell Calcium, 2003; 34:19-26
6 Weisser-Thomas J, Piacentino V 3rd, Gaughan JP, Margulies K, Houser SR Houser.Calcium entry via Na Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes[J].Cardiovasc Res, 2003; 57:974-85
7 Yoshiyama M, Nakamura Y, Omurat, Hayashit, Takagi Y, Hasegawa T, et al.Cardioprotective effect of SEA0400, a selective inhibitor of the Na⁺ Ca²⁺exchanger, on myocardial ischemia-reperfusion injury in rats[J].J Pharmacol Sci, 2004; 95:196-202
8 Nagasawa Y, Zhu BM, Chen J, Kamiya K, Miyamoto S, Hashimoto K.Effects of SEA0400, a Na⁺ Ca²⁺ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs[J].Eur J Pharmacol, 2005;506:249-55
9 Ohtsuka M, Takano H, Suzuki M, Zou Y, Akazawa H, Tamagawa M, et al.Role of Na⁺-Ca²⁺exchanger in myocardial ischemia reperfusion injury:evaluation using a heterozygous Na⁺-Ca²⁺exchanger knockout mouse model[J].Biochem Biophys Res Commun, 2004;314:849-53
10 Watanot, Harada Y, Harada K, Nishimura N.Effect of Na⁺ Ca²⁺ exchange inhibitor, KB-R7943 on ouabain-induced arrhythmias in guinea-pigs[J].Br J Pharmacol, 1999;127:1846-50
11 Amran MS, Hashimoto K, Homma N.Effects of sodium-calcium exchange inhibitors, KB-R7943 and SEA0400, on aconitine-induced arrhythmias in guinea pigs in vivo, in vitro, and in computer simulation studies[J].J Pharmacol Exp Ther, 2004;310:83-9
12 Nagy ZsA, Virág L, Tóth A, Biliczki P, Acsai K, Bányász T, et al.Selective inhibition of sodium-calcium exchanger by SEA-0400 decreases early and delayed afterdepolarization in canine heart[J].Br J Pharmacol, 2004;143:827-31
13 Olaf F.Ko¨ster, Gyula P.Szigeti, Dirk J.Beuckelmann. Characterization of a [Ca²⁺] i-dependent current in human atrial and ventricular cardiomyocytes in the absence of Na⁺ and K⁺[J].Cardiovasc Res, 1999;14:175-87
14 Janse MJ.Electrophysiological changes in heart failure and their relationship to arrhythmogenesis[J].Cardiovasc Res, 2004; 61:208-17
15 Iwamoto T, Watanot, Shigekawa M.A novel isothiourea derivative selectively inhibits the reverse mode of Na⁺ Ca²⁺ exchange in cells expressing NCX1[J].J Biol Chem, 1996;271: 22391-7
16 Takai N, Yamada A, Muraki K, Watanabe M, Imaizumi Y. KB-R7943 reveals possible involvement of Na⁺-Ca²⁺ exchanger in elevation of intracellular Ca²⁺ in rat carotid arterial myocytes[J].J SmoothMuscle Res, 2004;40:35-42
17 Iwamoto T, Kita S, Uehara A, Inoue Y, Taniguchi Y, Imanaga I, et al.Structural domains influencing sensitivity to isothiourea derivative inhibitor KB-R7943 in cardiac Na⁺ Ca²⁺exchanger[J].Mol Pharmacol, 2001;59:524-31
18 Hiroshi S, Masaaki M, Tsuyoshi U, Hideki K, Hajime T, Hideharu H.Importance of Ca²⁺influx by Na⁺ Ca²⁺ exchange under normal and sodium-loaded conditions in mammalian ventricles[J].Mol Cell Biochem, 2003;242:11-7
19 Satoh H, Ginsburg KS, Qing K, Terada H, Hayashi H, Bers DM.KB-R7943 block of Ca²⁺Influx via Na⁺ Ca²⁺exchange does not alter twitches or gly coside inotropy but prevents Ca²⁺overload in rat ventricular myocytes[J].Circulation, 2000; 101:1441-6
20 Miyamoto S, Zhu BM, Kamiya K, Nagasawa Y, Hashimoto K. KB-R7943, a Na⁺-Ca²⁺exchange inhibitor, does not suppress ischemia reperfusion arrhythmias nor digitalis arrhythmias in dogs[J].Jpn J Pharmacol, 2002;90:229-35
21 Matsuda T, Arakawa N, Takuma K, Kishida Y, Kawasaki Y, Sakaue M, et al.SEA0400, a novel and selective inhibitor of the Na⁺-Ca²⁺ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models[J].J Pharmacol Exp Ther, 2001;298:249-56
22 Takahashi K, Takahashit, Suzukit, Onishi M, Tanaka Y, Hamano-Takahashi A, et al.Protective effects of SEA0400, a novel and selective inhibitor of the Na⁺ Ca²⁺exchanger, on myocardial ischemia-reperfusion injuries[J].Eur J Pharmacol, 2003;458:155-62
23 Namekata I, Nakamura H, Shimada H, Tanaka H, Shigenobu K.Cardioprotection without cardiosuppression by SEA0400, a novel inhibitor of Na⁺-Ca²⁺ exchanger, during ischemia and reperfusion in guinea-pig myocardium [J].Life Sciences, 2005;77:312-24
24 Iwamoto T, Inoue Y, Ito K, Sakaue T, Kita S, Katsuragit. The exchanger inhibitory peptide region-dependent inhibition of Na⁺ Ca²⁺ exchange by SN-6 [2-[4-(4-nitrobenzyloxy) benzyl] thiazolidine-4-carboxylic acid ethyl ester], a novel benzyloxyphenyl derivative[J].Mol Pharmacol, 2004;66:45-55
25 Kuramochit, Kakefuda A, Yamada H, Tsukamoto I, Taguchit, Sakamoto S.Discovery of an N-(2-aminopy ridin-4-ylmethyl) nicotinamide derivative:a potent and orally bioavailable NCX inhibitor[J].Bioorg Med Chem, 2005;13:4022-36
26 Kuramochit, Kakefuda A, Yamada H, Tsukamoto I, Taguchit, Sakamoto S.Discovery of N-(3-{4-[(3-Fluoro-benzyl) oxy] phenoxy}propyl)-2-pyridin-4-ylacetamid-e as a potent and selective reverse NCX inhibitor[J].Chem Pharm Bull, 2005; 53:1043-7

[1]	张华斌, 罗中旭, 钟民, 洪宗元, 王德国. 脊髓麻醉对大鼠急性心肌缺血再灌注室性心律失常的影响研究[J]. 中国临床药理学与治疗学, 2023, 28(3): 249-256.
[2]	徐润泽, 韩静静, 李文倩, 杨劲. 从非临床到临床心律失常风险阶段评估体系研究进展[J]. 中国临床药理学与治疗学, 2021, 26(4): 423-433.
[3]	陈树儒, 路荣忠, 杜冠华, 赵玉军, 杨新博. 天然心房肽抗心律失常病例报道与机制分析[J]. 中国临床药理学与治疗学, 2021, 26(10): 1213-1214.
[4]	陈力方, 王博, 王维蓉. 组蛋白去乙酰化酶3在心血管疾病中的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(1): 88-97.
[5]	陈朝虎，庄华，姚志强，汉大黎，常成，马忠义，孔祥斌，曹金龙，李攀，田俊强. 钠钙交换体与肾缺血再灌注损伤[J]. 中国临床药理学与治疗学, 2019, 24(3): 355-360.
[6]	文继月，陈志武. 黄蜀葵花总黄酮对海马神经元缺氧复氧损伤的保护作用[J]. 中国临床药理学与治疗学, 2017, 22(4): 367-372.
[7]	何胜虎，周胜华，张晶,王雪飞,王大新. 急性ST段抬高型心肌梗死急诊PCI发生恶性心律失常临床特点及替罗非班的影响[J]. 中国临床药理学与治疗学, 2016, 21(4): 432-435.
[8]	后承林, 周炜, 卿恩明, 张铁铮, 刘功俭, 容俊芳, 武庆平, 郭曲练, 艾登斌, 金孝岠. 兰地洛尔治疗手术期心动过速性心律失常的多中心疗效和安全性评价[J]. 中国临床药理学与治疗学, 2015, 20(10): 1131-1136.
[9]	王蒙, 周建财, 张勇, 孙建国, 王广基. LC-MS/MS快速测定大鼠血浆中HHY-002浓度[J]. 中国临床药理学与治疗学, 2012, 17(11): 1206-1210.
[10]	范方田, 祝晓光, 李见春, 高署. LC-MS/MS法测定Beagle犬血浆中1-[4-(2,3-二氢-6-丙氧基)苯并吡喃]亚胺基-3-[3-(4-甲基哌嗪-1-基)丙基]-2,4-咪唑二酮的浓度及其生物利用度[J]. 中国临床药理学与治疗学, 2010, 15(5): 541-546.
[11]	申音, 邓婕, 宋洪涛. 药物基因组学与心律失常疾病的治疗[J]. 中国临床药理学与治疗学, 2010, 15(11): 1315-1320.
[12]	白霞, 郭志宏, 张璠, 范书铎. 短期禁食对大鼠心肌缺血再灌注心律失常及心肌能量代谢的影响[J]. 中国临床药理学与治疗学, 2009, 14(8): 900-905.
[13]	袁婷, 宋宏雁, 闫冬, 程路峰, 邹洲, 帕尔哈提·克热木. 舒必利致心律失常的电生理研究[J]. 中国临床药理学与治疗学, 2009, 14(4): 374-380.
[14]	曾雯君, 沈磊, 吴玉林. 钠钙交换体及其抑制剂在脑缺血中的作用[J]. 中国临床药理学与治疗学, 2009, 14(2): 237-240.
[15]	郑建发, 柯永胜. 心脏离子通道病的研究进展[J]. 中国临床药理学与治疗学, 2008, 13(4): 457-462.