药学学报

Active ingredient	Natural drug	Molecular formula	Antiarrhythmic type	Probable mechanism	State of evidence	Ref.
Alkaloid	Matrine	C₁₅H₂₄N₂O	Arrhythmias following myocardial infarction; AF	↓ I_Ca-L; ↑ I_Ca-L density, Cav1.2 protein	In vitro/animal models	[5, 6]
Oxymatrine	C₁₅H₂₄N₂O₂	Arrhythmias following myocardial infarction	↓ Cav1.2 mRNA	In vitro/animal models	[7]
Sophocarpine	C₁₅H₂₂N₂O	Experimental arrhythmia induced by ouabain and isoproterenol	↓ I_Ca-L	In vitro/animal models	[10-13]
Tetrandrine	C₃₈H₄₂N₂O₆	Early posterior depolarization and ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[18]
Isoliensinine	C₃₇H₄₂N₂O₆	Early post depolarization and late post depolarization	↓ I_Ca-L	In vitro	[20]
Dehydroevodiamine	C₁₉H₁₅N₃O	–	↓ I_Ca-L	In vitro	[22]
Changrolin	C₂₄H₂₉N₅O	–	↓ I_Ca	In vitro	[24]
Isorhynchophylline	C₂₂H₂₈N₂O₄	Experimental arrhythmias caused by ouabain and calcium chloride	↓ I_Ca	In vitro	[25]
Quinones	Tanshinone IIA	C₁₉H₁₈O₃	Long QT syndrome; ventricular arrhythmia following myocardial infarction	↓ CaM, CaMKII and LTCC mRNA	Animal models	[26, 27]
Tanshinone IIA sodium sulfonate	C₁₉H₁₇NaO₆S	Pathological Q waves	↓ CaM and CaMKII mRNA	Clinical research	[29]
Aloin	C₂₁H₂₂O₉	Experimental arrhythmias induced by aconitine, hypercalcium and ATX-II	↓ I_Ca-L	In vitro/animal models	[37]
Glycoside	Ginsenoside Re	C₄₈H₈₂O₁₈	–	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rb1	C₅₄H₉₂O₂₃	Late post depolarizing; ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[34]
Ginsenoside Rg1	C₄₂H₇₂O₁₄	Arrhythmia following I/R	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rg2	C₄₂H₇₂O₁₃	Experimental arrhythmia induced by CaCl₂	↓ CaMKII phosphorylation	Animal models	[37]
Paeoniflorin	C₂₃H₂₈O₁₁	–	↓ I_Ca-L	In vitro	[38]
Flavonoid	Icariin	C₃₃H₄₀O₁₅	Experimental arrhythmias induced by aconitine, isoproterenol, hypercalcium and ATX-II	↓ I_Ca-L	In vitro	[39]
Isovitexin	C₂₁H₂₀O₁₀	–	↓ I_Ca-L	In vitro	[40]
Resveratrol	C₁₄H₁₂O₃	VA and AVB following I/R	↓ I_Ca	In vitro	[42, 43]
Orientin	C₂₁H₂₀O₁₁	–	↓ I_Ca-L	In vitro	[44]
Terpenes	Schisandrin B	C₂₃H₂₈O₆	Experimental arrhythmias induced by aconitine	↓ I_Ca-L; ↓ calcium channel, recovery time	In vitro/animal models	[46]
Others	6-Gingerol	C₁₇H₂₆O₄	–	↓ I_Ca-L	In vitro	[47]
Paeonol	C₉H₁₀O₃	–	↓ I_Ca	In vitro	[48]
Crocetin	C₂₀H₂₄O₄	Experimental arrhythmias induced by aconitine, ouabain and calcium chloride	↓ I_Ca	In vitro	[50]
Nardosinone	C₁₅H₂₂O₃	–	↓ I_Ca-L	In vitro	[51]

Active ingredient	Natural drug	Molecular formula	Antiarrhythmic type	Probable mechanism	State of evidence	Ref.
Alkaloid	Matrine	C₁₅H₂₄N₂O	Arrhythmias following myocardial infarction; AF	↓ I_Ca-L; ↑ I_Ca-L density, Cav1.2 protein	In vitro/animal models	[5, 6]
Oxymatrine	C₁₅H₂₄N₂O₂	Arrhythmias following myocardial infarction	↓ Cav1.2 mRNA	In vitro/animal models	[7]
Sophocarpine	C₁₅H₂₂N₂O	Experimental arrhythmia induced by ouabain and isoproterenol	↓ I_Ca-L	In vitro/animal models	[10-13]
Tetrandrine	C₃₈H₄₂N₂O₆	Early posterior depolarization and ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[18]
Isoliensinine	C₃₇H₄₂N₂O₆	Early post depolarization and late post depolarization	↓ I_Ca-L	In vitro	[20]
Dehydroevodiamine	C₁₉H₁₅N₃O	–	↓ I_Ca-L	In vitro	[22]
Changrolin	C₂₄H₂₉N₅O	–	↓ I_Ca	In vitro	[24]
Isorhynchophylline	C₂₂H₂₈N₂O₄	Experimental arrhythmias caused by ouabain and calcium chloride	↓ I_Ca	In vitro	[25]
Quinones	Tanshinone IIA	C₁₉H₁₈O₃	Long QT syndrome; ventricular arrhythmia following myocardial infarction	↓ CaM, CaMKII and LTCC mRNA	Animal models	[26, 27]
Tanshinone IIA sodium sulfonate	C₁₉H₁₇NaO₆S	Pathological Q waves	↓ CaM and CaMKII mRNA	Clinical research	[29]
Aloin	C₂₁H₂₂O₉	Experimental arrhythmias induced by aconitine, hypercalcium and ATX-II	↓ I_Ca-L	In vitro/animal models	[37]
Glycoside	Ginsenoside Re	C₄₈H₈₂O₁₈	–	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rb1	C₅₄H₉₂O₂₃	Late post depolarizing; ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[34]
Ginsenoside Rg1	C₄₂H₇₂O₁₄	Arrhythmia following I/R	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rg2	C₄₂H₇₂O₁₃	Experimental arrhythmia induced by CaCl₂	↓ CaMKII phosphorylation	Animal models	[37]
Paeoniflorin	C₂₃H₂₈O₁₁	–	↓ I_Ca-L	In vitro	[38]
Flavonoid	Icariin	C₃₃H₄₀O₁₅	Experimental arrhythmias induced by aconitine, isoproterenol, hypercalcium and ATX-II	↓ I_Ca-L	In vitro	[39]
Isovitexin	C₂₁H₂₀O₁₀	–	↓ I_Ca-L	In vitro	[40]
Resveratrol	C₁₄H₁₂O₃	VA and AVB following I/R	↓ I_Ca	In vitro	[42, 43]
Orientin	C₂₁H₂₀O₁₁	–	↓ I_Ca-L	In vitro	[44]
Terpenes	Schisandrin B	C₂₃H₂₈O₆	Experimental arrhythmias induced by aconitine	↓ I_Ca-L; ↓ calcium channel, recovery time	In vitro/animal models	[46]
Others	6-Gingerol	C₁₇H₂₆O₄	–	↓ I_Ca-L	In vitro	[47]
Paeonol	C₉H₁₀O₃	–	↓ I_Ca	In vitro	[48]
Crocetin	C₂₀H₂₄O₄	Experimental arrhythmias induced by aconitine, ouabain and calcium chloride	↓ I_Ca	In vitro	[50]
Nardosinone	C₁₅H₂₂O₃	–	↓ I_Ca-L	In vitro	[51]

植物源天然钙离子通道拮抗剂在抗心律失常药物开发中的应用研究进展

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蒲利华 ¹^,² , 贺爽 ¹^,² , 周正灿 ¹^,² , 朱彦 ¹^,²^,^*

药学学报 | 专题报道Ⅱ：中药防治心脑相关疾病 2022,57(10): 3027-3034

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药学学报 | 专题报道Ⅱ：中药防治心脑相关疾病 2022, 57(10): 3027-3034

植物源天然钙离子通道拮抗剂在抗心律失常药物开发中的应用研究进展

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蒲利华¹^,², 贺爽¹^,², 周正灿¹^,², 朱彦¹^,²^,^*

作者信息

1.天津中医药大学组分中药国家重点实验室, 天津 301617

2.天津国际生物医药联合研究院中药新药研发中心, 天津 300457

通讯作者:

*朱彦, Tel: 15822700439, Fax: 86-22-27429103, E-mail: yanzhu.harvard@icloud.com

Research progress on applying plant-derived natural calcium channel blockers in the antiarrhythmic drug development

Li-hua PU¹^,², Shuang HE¹^,², Zheng-can ZHOU¹^,², Yan ZHU¹^,²^,^*

Affiliations

1. State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China

2. Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, China

出版时间: 2022-10-12 doi: 10.16438/j.0513-4870.2022-0284

文章导航

摘要

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心律失常是心脏活动的起源和/或传导障碍导致的心脏搏动频率和/或节律异常。心律失常疾病表现多样且病因复杂, 可单独发生, 也可与其他心血管疾病并发; 可突然发作导致猝死, 也可持续发作导致心力衰竭。在心肌细胞中, 钙超载可诱导细胞凋亡, 导致心律失常的发生。钙通道阻滞剂作为调节钙信号的心血管常规药物已在临床广泛使用, 但其对不同心律失常并发症的疗效不尽相同, 且具有潜在的治疗风险。因此, 从植物和其他天然产物资源寻求针对新作用机制和靶标的钙离子信号调节剂并将其开发为安全性更高、疗效更为显著的心律失常治疗药物意义重大。本文着眼于植物源天然钙离子通道拮抗剂对心律失常模型中钙离子信号的调控作用, 对近年的研究成果进展予以综述, 汇总了通过调控Ca²⁺稳态而抗心律失常的生物碱、皂苷、醌类和黄酮类化合物等多种天然药物的作用和机制, 以期为今后运用天然产物钙离子通道拮抗剂防治心律失常进行的药物开发提供理论依据。

关键词

心律失常 / 钙离子通道拮抗剂 / 天然药物 / 生物活性成分 / 钙信号

Abstract

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Arrhythmia is the abnormal heart-beat frequency and/or rhythm caused by the origin of cardiac activity and/or conduction disorder. Arrhythmia disease has various manifestations and complex etiology, which can occur alone or complicated with other cardiovascular diseases. A sudden arrhythmic onset may lead to sudden death, whereas a sustained onset may lead to heart failure. In cardiomyocytes, calcium overload induces apoptosis and leads to arrhythmia. Calcium channel blockers have been widely used in clinic as a routine cardiovascular drug to regulate calcium signal, but their efficacy on different arrhythmia complications vary, and they also have potential therapeutic risks. Therefore, it is of great significance to seek calcium signal modulators targeting new mechanisms from plants and other natural product resources and develop them into anti-arrhythmia drugs with higher safety and better curative effect. This review focuses on the calcium signal regulatory effects of plant-derived natural calcium channel antagonists in arrhythmia models, highlights the research progress in recent years, and summarizes the effects and mechanisms of various natural drugs such as alkaloids, saponins, quinones and flavonoids, which regulate Ca²⁺ homeostasis, to provide a theoretical basis for the drug development of natural calcium channel antagonists to prevent and treat arrhythmia in the future.

Key words

arrhythmia / calcium channel blocker / natural medicine / bioactive ingredient / calcium signal

引用本文

蒲利华, 贺爽, 周正灿, 朱彦. 植物源天然钙离子通道拮抗剂在抗心律失常药物开发中的应用研究进展. 药学学报, 2022 , 57 (10) : 3027 -3034 . DOI: 10.16438/j.0513-4870.2022-0284

Li-hua PU, Shuang HE, Zheng-can ZHOU, Yan ZHU. Research progress on applying plant-derived natural calcium channel blockers in the antiarrhythmic drug development[J]. Acta Pharmaceutica Sinica, 2022 , 57 (10) : 3027 -3034 . DOI: 10.16438/j.0513-4870.2022-0284

正文

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钙是生物体内重要的元素之一。在心律失常患者中, Ca²⁺调控异常所致的病理性重构可进一步促进心律失常的发生^{[1, 2]}。目前已批准的针对Ca²⁺治疗心律失常的药物主要为Ca²⁺通道阻滞剂, 如维拉帕米等。然而, 尽管Ca²⁺通道阻滞剂对某些心律失常起效, 但应用范围有限, 如不宜用于心力衰竭患者抗心律失常的治疗, 从而缩小了其应用范围^[3]。

天然产物Ca²⁺通道拮抗剂可在一定程度上抑制心律失常的发生, 通过在PubMed (https://pubmed.ncbi.nlm.nih.gov/) 和中国知网(https://www.cnki.net/) 搜索关于天然药物治疗心律失常不同机制研究的文章, 本综述汇总了通过调控Ca²⁺稳态而抗心律失常的生物碱、皂苷等多种天然药物的作用和机制, 以期为抗心律失常药物的进一步研究提供参考。

1 生物碱

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1.1 喹诺里西啶类生物碱

苦参总碱广泛存在于苦参、苦豆子等豆科植物中, 主要含有苦参碱(matrine, MAT)、氧化苦参碱(oxymatrine, OMT)、槐果碱(sophocarpine, Soph)、槐定碱等多种单体, 以MAT、OMT含量最高。MAT是目前临床应用最广泛、研究最多的一种苦参碱类生物碱。哇巴因(ouabain) 在心律失常和心脏毒性评价中常被用于造模, 其诱发心律失常的机制为诱导细胞内的钙超载, 在10 μmol·L^-1浓度下可使豚鼠心肌细胞动作电位时程(action potential duration, APD) 延长80%, 并增加KCl诱导的L型钙电流(I_Ca-L) 和Ca²⁺瞬变^[4]。静脉注射苦参碱可显著且剂量依赖性地增加哇巴因诱导豚鼠室性早搏的剂量, 缩短其诱导的心律失常持续时间。在豚鼠心肌细胞中, 100 μmol·L^-1苦参碱可明显缩短哇巴因引起延长的APD, 并阻止哇巴因诱导的I_Ca-L内流和Ca²⁺瞬变增加。MAT可能通过竞争哇巴因的结合位点而抑制I_Ca-L并防止钙超载的发生^[5]。且MAT预处理15天可剂量依赖性地显著降低小鼠电起搏致房颤的发生率和持续时间, 作用机制为上调小鼠心房细胞膜I_Ca-L密度和Cav1.2蛋白表达密度^[6]。由此可见, MAT对心房肌细胞、心室肌细胞均有调节作用, 且调节机制并不相同, 是很有前途的抗心律失常潜在药物。

研究发现OMT预处理不仅可拮抗乌头碱引起的心律失常, 增加乌头碱诱导大鼠心律失常所需的剂量, 还可剂量依赖性(3、10和30 mg·kg^-1) 延缓冠脉结扎所致大鼠心律失常的发生时间, 缩短其持续时间, 降低死亡率, 电生理研究表明OMT能浓度依赖性地显著抑制离体大鼠心肌细胞钠、钙电流^[7]。且OMT可降低心肌L型钙通道Cav1.2 mRNA的表达^[8], 降低心肌Cx43的表达^[9], 降低心梗大鼠心肌的损伤和心律失常的发生率。MAT和OMT具有相同的抗心律失常作用, 部分原因是其结构相似。OMT在体内可被代谢为MAT, 故OMT是否能拮抗房颤的发生仍值得探索。

Soph对多种心律失常均有抑制作用。研究发现Soph可抑制静脉注射乌头碱诱发的豚鼠室早、室速、室扑、室颤, 提高造成心脏停搏所需的乌头碱累积量^[10]。研究表明, 心肌细胞晚钠电流(I_Na-L) 的增加导致细胞内Na⁺超载, 并随后增大Na⁺/Ca²⁺交换体电流(I_NCX), 最终导致细胞内Ca²⁺超载^[11]。在兔心室肌细胞中, Soph (20、40和80 μmol·L^-1) 以浓度依赖性方式抑制I_Na-L、I_NCX和Ca²⁺浓度, 加快心肌舒张速度, 防止细胞内Ca²⁺超载, 预防心律失常的发生和心肌细胞的损伤^[12]。通过离体心脏灌流和膜片钳研究发现, Soph (300 μmol·L^-1) 能拮抗(15 μmol·L^-1) 异丙肾上腺素引起的心律失常, 抑制I_Na、I_Ca-L和快激活延迟整流钾通道电流(I_Kr), 延长APD₉₀和有效不应期(effective refractory period, ERP)^[13]。Soph电生理作用与胺碘酮相似, 可通过调节多种离子通道预防心律失常的发生, 是一种有前景的抗心律失常潜在药物。

1.2 异喹啉类生物碱

粉防己碱(tetrandrine, Tet) 为防己的有效生物活性成分之一。研究发现, Tet及其衍生物在心血管保护方面具有显著作用, 研究者尤为关注Tet的抗心律失常作用^{[14, 15]}。Tet可有效抑制前负荷增加引起APD延长和ERP缩短, 降低振幅和室颤阈。因此Tet可能是通过阻滞牵张激活性离子通道, 从而抑制前负荷增加引起的心肌电生理特性改变^[16]。通过豚鼠心肌缺血再灌注损伤模型, 研究者发现Tet可明显减少再灌注早期心交感神经递质去甲肾上腺素的释放, 减少室颤的发生^[17]。Jiang等^[18]研究发现Tet (0.5 mg·kg^-1·min^-1恒速静脉给药, 共10 min) 可拮抗氯化铯(1.5 mmol·kg^-1) 诱发早期后除极及室性心律失常的作用, 其作用机制可能是Tet抑制慢钙通道, 减少内向电流。由此可见, Tet不仅可影响心肌中的Ca²⁺浓度, 还可通过多靶点达到抗心律失常的作用。

异莲心碱存在于莲子植物睡莲科的胚芽中, 在抗氧化、抗癌等方面有一定作用^[19]。研究发现^[20], 异莲心碱可通过抑制峰钠电流(I_Na-P)、I_Ca-L和I_Na-L消除早期后除极和晚期后除极的发生来发挥其抗心律失常的作用。

1.3 喹唑啉类生物碱

去氢吴茱萸碱(dehydroevodiamine, Deh) 是从吴茱萸中分离出的喹唑啉类生物碱, 对豚鼠心室肌细胞具有抗心律失常作用。Deh可通过减少Na⁺和Ca²⁺内向电流, 增加静息状态下细胞内液的pH值和Na⁺-H⁺交换, 产生抗心律失常作用^[21]。Deh还可通过延长实验动物心肌细胞的APD, 抑制钙超载引发的心律失常^[22]。但也有研究指出, 因为上述抗心律失常药物浓度与其阻滞I_kr药物浓度相近, 故使用Deh时应警惕致心律失常作用^[23]。

此外, 常山乙素的衍生物changroli被证实不仅可抑制I_Ca, 还对其他离子通道I_Na、I_K和I_to均具有抑制作用^[24], 可改变心脏电生理, 预防心律失常的发生。

1.4 吲哚类生物碱

异钩藤碱为中药钩藤的主要活性成分之一, 具有一定的抗心律失常作用, 其可拮抗哇巴因和氯化钙引起的在体实验性心律失常, 呈剂量依赖性显著降低离体豚鼠和大鼠心肌细胞的APD, 其作用机制与抑制钙电流有关^[25]。

对于拮抗心律失常, 生物碱类单体可多层次、多靶点发挥作用, 包括抑制Ca²⁺通道和Na⁺通道、抗氧化应激和抗炎等, 具有良好的应用前景。然而, 各个单体在个体水平上的研究较为薄弱, 特别是体内药动学研究和安全性评价等, 以及天然产物单体与靶点直接相互作用的研究非常少, 对于生物碱这些反应发生机制中靶点的相关性及临床用药安全性有待进一步研究。

2 醌类化合物

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丹参酮IIA为丹参的主要活性成分, 其抗心律失常作用在多种心律失常模型中都得到验证。研究发现丹参酮IIA在兔离体心脏2型长QT综合征模型中可显著缩短LQT 2 (long QT 2) 的QT间期, 左心室内、外膜的APD₉₀和ERP, 降低室性心动过速的诱发率^[26]。细胞内钙超载可激活钙/钙调素依赖性蛋白激酶II (CaMKII), 增加I_Na-L, 形成恶性循环。因此, 抑制CaMKII通路是减少钙超载引起心律失常的一个治疗靶点。在兔急性心肌梗死后室性心律失常模型中, 丹参酮IIA组的偶发室性早搏、频发室性早搏、室性心动过速发生率明显下降, 其心肌钙调蛋白(CaM)、CaMKII及L型电压门控钙通道(voltage-gated L-type Ca²⁺ channel, LTCC) 的mRNA表达较梗死组明显降低^[27]。研究者认为丹参酮IIA显著降低急性心肌梗死室性心律失常发生率的分子机制可能与钙调蛋白及相关离子通道蛋白基因的表达变化有关, 且发现临床中急性心梗患者再灌注治疗的同时静脉给药丹参酮IIA磺酸钠, 将有效降低患者发生室性心律失常的可能性^[28]。此外, 研究发现丹参酮IIA磺酸钠注射液不仅对肾血管性高血压有确切的治疗作用, 还可下调肾血管性高血压患者心肌CaM及CaMKII的mRNA表达, 阻断Ca²⁺/CaM-CaMKII信号传导通路, 抑制病理性Q波出现, 进而减少患者并发心律失常的可能^[29]。

芦荟苷具有抗炎、抗肿瘤等多种生物活性^[30], 研究者近来发现其可通过调节多种离子电流发挥抗心律失常作用。Cao^[31]发现芦荟苷可有效消除兔的心室肌细胞的早期后除极和延迟后除极, 抑制I_Ca-L、I_Na-P及海葵毒素II (Anemonia sulcate toxin Ⅱ, ATX-II) 诱导增大的I_Na-L, 同时其还能抑制乌头碱诱导的心律失常发生。因此, 芦荟苷是一种低成本、安全性高、有前景的抗心律失常药物。

3 苷类化合物

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研究发现人参可从多离子通道阻滞作用、抑制炎症反应、调节自主神经等多方面减少心律失常的发生^[32]。人参皂苷为人参中的主要活性成分, 可通过抑制Ca²⁺通道, 调节细胞内的Ca²⁺信号发挥抗心律失常的功效。Cao等^[33]采用异丙肾上腺素诱导离体大鼠心脏心律失常模型, 证实人参皂苷Re对原代乳鼠心肌细胞无明显的毒性, 且可通过调节cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A) 通路和抑制炎性反应减少快速型心律失常的发生。通过膜片钳技术探究人参皂苷Re调节心脏离子电流的潜在机制, 发现人参皂苷Re通过cGMP依赖性通路抑制I_Ca-L^[34]。

人参皂苷Rg1对大鼠心肌缺血再灌注(I/R) 后的心律失常具有调节作用^[35]。研究者采用冠状动脉左前降支结扎的方法建立I/R模型。Rg1组的心律失常明显改善, 心肌I/R面积、心肌酶及炎症因子表达水平均明显降低。Rg1可通过抑制PPAR-γ介导的炎症反应来改善大鼠心肌I/R后心律失常。而Yang等^[36]采用全细胞膜片钳技术发现人参皂苷Rg1和Re配伍后会协同增强对I_Ca-L的抑制作用。

人参皂苷Rg2可显著下调CaCl₂诱导的心律失常大鼠心脏CaMKII磷酸化, 调节LTCC活性, 抑制Ca²⁺内流, 减少心律失常的发生^[37]。

人参皂苷Rb1的研究具有较大争议, 有研究报道人参皂苷Rb1 (10、100 μmol·L^-1) 对I_Ca-L电流幅度无明显影响^[36], 另有研究发现其可浓度依赖性地抑制I_Ca-L, 且人参皂苷Rb1 (80 μmol·L^-1) 可使L型钙电流稳态失活曲线左移, 但不影响稳态失活曲线, 人参皂苷Rb1 (40 μmol·L^-1) 可降低缺血再灌注损伤引发的室性早搏次数, 延迟室性早搏的首发时间, 进而降低室性心动过速的发生率^[20]。因此人参皂苷Rb1的不同浓度对于心肌细胞的影响需进一步探究。

芍药苷来源于芍药科植物芍药的根等。研究者采用全细胞膜片钳技术发现芍药苷可通过抑制I_Ca-L减少振荡后电位或期外收缩来预防心律失常的发生^[38]。

苷类化合物属大分子化合物, 是由糖或糖衍生物的端基碳原子与另一类非糖物质(甙元) 连接形成的化合物。植物体内存在且在生物体内发挥药效的多为一级苷, 当苷类水解成甙元后, 在水中的溶解度与疗效将大为降低, 因此含甙类成分的中草药(如人参) 等, 在采集、加工、贮藏与制造含甙类成分的中草药(如人参) 时, 必须注意防止水解。另外, 当在考虑药物单体制作为中成药时, 应考虑中药的配伍理论, 使不同的单体可发挥协同作用(如上述人参皂苷Rg1和Re配伍后可增强对I_Ca-L的抑制作用)。

4 黄酮类化合物

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淫羊藿苷是从中药淫羊藿中提取的一种黄酮类化合物。淫羊藿苷可降低乌头碱诱发新西兰大耳朵兔心律失常的发生率, 抑制异丙肾上腺素和高钙引起的左心室肌细胞的迟后除极和触发激动及ATX-II引起的早后除极, 显著提高大耳兔的存活率。通过膜片钳技术记录的左心房肌细胞和左心室肌细胞的离子通道和动作电位, 发现淫羊藿苷作用机制为抑制左心房肌细胞和左心室肌细胞的I_Na-L和I_Ca-L发挥抗心律失常作用^[39]。另外研究发现异牡荆素可影响大鼠心室肌细胞I_Na、I_to、I_Ca-L电流, 为其抗心律失常作用提供了理论依据^[40]。

白藜芦醇(resveratrol, RES) 可从葡萄(红酒)、花生、桑葚等植物中提取, 具有很强的生物活性^[41], 可降低大鼠心肌缺血再灌注后室性心律失常、房室传导阻滞的发生率和致死率^[42]。电生理实验表明RES可抑制内向钠电流和钙电流, 增加ERP^[43]。因此, 日常多食用含有RES的食物对身体有益。

荭草苷是一种天然存在的生物活性类黄酮, 主要存在于刚竹属竹叶等药用植物中。研究者发现其可抑制心肌细胞离子电流(I_Na、I_to和I_Ca-L), 并能使其通道动力学特征发生改变^[44]。因此, 研究者认为此结果与其抗心律失常的作用有关。

黄酮类化合物是一种植物生长中产生的次级代谢产物, 一般其与糖苷相结合, 具有较复杂的分子结构, 但由于其溶解性差、稳定性不好等导致其生物利用率较低, 目前通过结构修饰改善其生物活性的探究正在进行, 有望改善其缺点, 扩大应用。

5 萜类化合物

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五味子乙素(schisandrin B, Sch B) 是从五味子中分离的联苯环辛二烯衍生物, 对心脏具有抗氧化作用^[45]。Sch B可拮抗乌头碱引起的心律失常作用, 其作用机制为抑制离子电流I_Na、I_to和I_Ca-L, 改变其通道动力学的特征^[46]。

6 其他

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6-姜酚(6-Gin) 为姜的主要成分之一, 可治疗多种心血管疾病。通过膜片钳技术和Ion Optix系统研究认为, 6-Gin可减弱缺血心肌细胞的I_Ca-L, 抑制心脏收缩功能^[47]。这些研究结果为进一步研究6-Gin作为抗心律失常候选药物的药理作用提供了新的视角。

丹皮酚(paeonol, Pae) 药理作用广泛, 对各类心血管疾病和神经系统疾病等疗效确切。研究者利用膜片钳全细胞技术发现Pae可明显缩短心肌细胞的APD, 且浓度依赖性地阻滞I_Ca, 为其抗心律失常作用的主要机制之一^[48]。但Pae自身水溶性差、代谢迅速的特点限制了临床应用, 期待Pae的多方向剂型开发能为其抗心律失常的应用带来更广阔的应用前景。

藏红花酸为藏红花素的次级代谢产物, 对心肌缺血^[49]、心律失常^[50]等多种心血管疾病均有保护作用。研究发现藏红花酸对多种实验性心律失常模型具有拮抗作用, 高、中、低剂量藏红花酸(10、20、40 mg·kg^-1) 均可提高由乌头碱所致大鼠心律失常的用量, 也可提高哇巴因所致豚鼠心律失常的用量, 并可显著降低氯化钙诱导大鼠室颤或室早的发生率及死亡率^[50], 其抗心律失常的作用机制可能与其抑制Na⁺或Ca²⁺内流等因素有关。藏红花酸用于心律失常的治疗, 可有效抑制室速、室颤等现象的出现, 降低心律失常对于患者的伤害。

除上述中药来源的单体化合物(总结于表 1^{[5-7, 10-13, 18, 20, 22, 24-27, 29, 34, 36-40, 42-44, 46-48, 50, 51]}和图 1), 通常以复方用药的中药可能存在多种Ca²⁺通道拮抗剂, 它们之间的协同作用不容忽视, 如稳心颗粒由党参、黄精、三七、琥珀、甘松5种中药组成, 具有良好的抗心律失常疗效^{[52, 53]}。如上述研究中提到的人参皂苷Re、人参皂苷Rb1等均为稳心颗粒的物质基础。而甘松新酮^[54]为使药甘松的有效活性成分, 研究发现其可抑制心室肌的主要离子通道(I_Na、I_to、I_Ca-L), 对心脏电生理的影响可能是其抗心律失常的机制之一。

7 总结与展望

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在过去的几十年里, 心律失常的病理机制研究有了显著进展。虽然心律失常的具体分子机制多种多样, 但Ca²⁺在其中扮演了关键角色。心律失常的研究使人们对心肌细胞的生理和病理调节有了新认识。基因测序平台的快速发展及最近在体外和体内疾病模型开发方面的突破都将有助于心律失常相关疾病的诊断和治疗, 同时为抗心律失常药物的研发提供了新的靶点。

值得注意的是, 目前临床常用的抗心律失常药物都具有一定潜在的致心律失常作用, 因此仍迫切需要寻找更安全的抗心律失常药物。天然药物单体的作用靶点多, 其作用机制相对复杂, 如上文提到的人参皂苷可从调节多种离子通道结合抗炎的作用机制预防心律失常的发生, 减少只作用于单一离子通道潜在的致心律失常作用。从目前已发表的文献来看, 临床用于治疗心律失常的多为中药复方及中成药, 如稳心颗粒^[53]、心速宁胶囊^[55]等复方中药, 均含有上述某单体, 在临床具有广泛应用。但对于天然药物单体的研究更多的是利用膜片钳等技术, 作用机制大多停留在离子通道, 并没有进行更深入的研究。研究者应整合当前在心脏分子生物学、生物化学等方面的最新成果, 构建从离子通道、细胞、组织、离体器官到整体多个层次的模型, 用于系统研究微观局部变化到宏观抗心律失常表现的过程, 改变传统细胞离子通道、整体动物及临床表现单独研究心律失常的方式, 实现微观与宏观研究的统一。

新近临床研究发现, 丹参酮IIA磺酸钠可与多种临床抗心律失常药物联用, 治疗心律失常更加安全有效。当丹参酮IIA磺酸钠联合胺碘酮治疗急性心肌梗死并心房颤动, 患者的房颤转复有效率、房颤复发率、心力衰竭发生率、死亡率、不良反应率等均优于胺碘酮单药^[56]。此外, 丹参酮IIA磺酸钠与稳心颗粒联用也有报道, 其效果优于单药^[57]。现今天然药物单体抗心律失常研究更多停留在实验研究方面, 未在抗心律失常方面具有更广泛的临床应用, 如以粉防己碱为主要成分的汉防己甲素片, 虽通过动物实验与膜片钳技术认为其确有抗心律失常作用, 但其在临床主要适用症为疼痛、抗癌与硅肺, 不过粉防己碱的各种新剂型如缓释制剂、靶向制剂也有陆续报道^[57], 也许其抗心律失常作用应用于临床指日可待。

提取技术工艺是造成部分的天然药物单体难以获取的原因, 很难进行临床试验研究或研究样本数量较少, 没有明确的纳入与排除标准, 且临床研究中多以心电图为评价依据, 说服力不强。而且在临床研究中, 心律失常的疗效判定缺乏统一的标准, 不利于药品的筛选和疗效评价。在今后的研究中, 应制定相对统一完善的中药研究的方法及标准, 改善工艺方法, 以利于天然药物单体的提取制备, 对相关药物进行更加深入的研究, 明确每种单体的作用, 在探讨天然产物Ca²⁺通道拮抗剂治疗心律失常的同时, 也应关注其潜在不良反应, 以更好地指导临床, 发挥天然产物的巨大作用。

作者贡献: 蒲利华负责撰写与修改文章; 贺爽、周正灿参与了数据采集及整理; 朱彦负责指导写作及修改文章。

利益冲突: 所有作者均声明不存在任何利益冲突。

基金

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国家重点研发计划项目(2018YFC1704502)
国家自然科学基金资助项目(81873037)
国家科技重大专项资助项目(2018ZX01031301)

参考文献

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2022年第57卷第10期

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doi: 10.16438/j.0513-4870.2022-0284

接收时间：2022-03-04
首发时间：2025-12-24
出版时间：2022-10-12

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收稿日期：2022-03-04
修回日期：2022-04-04

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国家重点研发计划项目(2018YFC1704502)

国家自然科学基金资助项目(81873037)

国家科技重大专项资助项目(2018ZX01031301)

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1.天津中医药大学组分中药国家重点实验室, 天津 301617

2.天津国际生物医药联合研究院中药新药研发中心, 天津 300457

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*朱彦, Tel: 15822700439, Fax: 86-22-27429103, E-mail: yanzhu.harvard@icloud.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Active ingredient	Natural drug	Molecular formula	Antiarrhythmic type	Probable mechanism	State of evidence	Ref.
Alkaloid	Matrine	C₁₅H₂₄N₂O	Arrhythmias following myocardial infarction; AF	↓ I_Ca-L; ↑ I_Ca-L density, Cav1.2 protein	In vitro/animal models	[5, 6]
Oxymatrine	C₁₅H₂₄N₂O₂	Arrhythmias following myocardial infarction	↓ Cav1.2 mRNA	In vitro/animal models	[7]
Sophocarpine	C₁₅H₂₂N₂O	Experimental arrhythmia induced by ouabain and isoproterenol	↓ I_Ca-L	In vitro/animal models	[10-13]
Tetrandrine	C₃₈H₄₂N₂O₆	Early posterior depolarization and ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[18]
Isoliensinine	C₃₇H₄₂N₂O₆	Early post depolarization and late post depolarization	↓ I_Ca-L	In vitro	[20]
Dehydroevodiamine	C₁₉H₁₅N₃O	–	↓ I_Ca-L	In vitro	[22]
Changrolin	C₂₄H₂₉N₅O	–	↓ I_Ca	In vitro	[24]
Isorhynchophylline	C₂₂H₂₈N₂O₄	Experimental arrhythmias caused by ouabain and calcium chloride	↓ I_Ca	In vitro	[25]
Quinones	Tanshinone IIA	C₁₉H₁₈O₃	Long QT syndrome; ventricular arrhythmia following myocardial infarction	↓ CaM, CaMKII and LTCC mRNA	Animal models	[26, 27]
Tanshinone IIA sodium sulfonate	C₁₉H₁₇NaO₆S	Pathological Q waves	↓ CaM and CaMKII mRNA	Clinical research	[29]
Aloin	C₂₁H₂₂O₉	Experimental arrhythmias induced by aconitine, hypercalcium and ATX-II	↓ I_Ca-L	In vitro/animal models	[37]
Glycoside	Ginsenoside Re	C₄₈H₈₂O₁₈	–	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rb1	C₅₄H₉₂O₂₃	Late post depolarizing; ventricular arrhythmias	↓ I_Ca-L	In vitro/animal models	[34]
Ginsenoside Rg1	C₄₂H₇₂O₁₄	Arrhythmia following I/R	↓ I_Ca-L	In vitro	[36]
Ginsenoside Rg2	C₄₂H₇₂O₁₃	Experimental arrhythmia induced by CaCl₂	↓ CaMKII phosphorylation	Animal models	[37]
Paeoniflorin	C₂₃H₂₈O₁₁	–	↓ I_Ca-L	In vitro	[38]
Flavonoid	Icariin	C₃₃H₄₀O₁₅	Experimental arrhythmias induced by aconitine, isoproterenol, hypercalcium and ATX-II	↓ I_Ca-L	In vitro	[39]
Isovitexin	C₂₁H₂₀O₁₀	–	↓ I_Ca-L	In vitro	[40]
Resveratrol	C₁₄H₁₂O₃	VA and AVB following I/R	↓ I_Ca	In vitro	[42, 43]
Orientin	C₂₁H₂₀O₁₁	–	↓ I_Ca-L	In vitro	[44]
Terpenes	Schisandrin B	C₂₃H₂₈O₆	Experimental arrhythmias induced by aconitine	↓ I_Ca-L; ↓ calcium channel, recovery time	In vitro/animal models	[46]
Others	6-Gingerol	C₁₇H₂₆O₄	–	↓ I_Ca-L	In vitro	[47]
Paeonol	C₉H₁₀O₃	–	↓ I_Ca	In vitro	[48]
Crocetin	C₂₀H₂₄O₄	Experimental arrhythmias induced by aconitine, ouabain and calcium chloride	↓ I_Ca	In vitro	[50]
Nardosinone	C₁₅H₂₂O₃	–	↓ I_Ca-L	In vitro	[51]

Active ingredient

Natural drug

Molecular formula

Antiarrhythmic type

Probable mechanism

State of evidence

Ref.

Alkaloid

Matrine

C₁₅H₂₄N₂O

Arrhythmias following myocardial infarction; AF

↓ I_Ca-L; ↑ I_Ca-L density, Cav1.2 protein

In vitro/animal models

[5, 6]

Oxymatrine

C₁₅H₂₄N₂O₂

Arrhythmias following myocardial infarction

↓ Cav1.2 mRNA

In vitro/animal models

[7]

Sophocarpine

C₁₅H₂₂N₂O

Experimental arrhythmia induced by ouabain and isoproterenol

↓ I_Ca-L

In vitro/animal models

[10-13]

Tetrandrine

C₃₈H₄₂N₂O₆

Early posterior depolarization and ventricular arrhythmias

↓ I_Ca-L

In vitro/animal models

[18]

Isoliensinine

C₃₇H₄₂N₂O₆

Early post depolarization and late post depolarization

↓ I_Ca-L

In vitro

[20]

Dehydroevodiamine

C₁₉H₁₅N₃O

–

↓ I_Ca-L

In vitro

[22]

Changrolin

C₂₄H₂₉N₅O

–

↓ I_Ca

In vitro

[24]

Isorhynchophylline

C₂₂H₂₈N₂O₄

Experimental arrhythmias caused by ouabain and calcium chloride

↓ I_Ca

In vitro

[25]

Quinones

Tanshinone IIA

C₁₉H₁₈O₃

Long QT syndrome; ventricular arrhythmia following myocardial infarction

↓ CaM, CaMKII and LTCC mRNA

Animal models

[26, 27]

Tanshinone IIA sodium sulfonate

C₁₉H₁₇NaO₆S

Pathological Q waves

↓ CaM and CaMKII mRNA

Clinical research

[29]

Aloin

C₂₁H₂₂O₉

Experimental arrhythmias induced by aconitine, hypercalcium and ATX-II

↓ I_Ca-L

In vitro/animal models

[37]

Glycoside

Ginsenoside Re

C₄₈H₈₂O₁₈

–

↓ I_Ca-L

In vitro

[36]

Ginsenoside Rb1

C₅₄H₉₂O₂₃

Late post depolarizing; ventricular arrhythmias

↓ I_Ca-L

In vitro/animal models

[34]

Ginsenoside Rg1

C₄₂H₇₂O₁₄

Arrhythmia following I/R

↓ I_Ca-L

In vitro

[36]

Ginsenoside Rg2

C₄₂H₇₂O₁₃

Experimental arrhythmia induced by CaCl₂

↓ CaMKII phosphorylation

Animal models

[37]

Paeoniflorin

C₂₃H₂₈O₁₁

–

↓ I_Ca-L

In vitro

[38]

Flavonoid

Icariin

C₃₃H₄₀O₁₅

Experimental arrhythmias induced by aconitine, isoproterenol, hypercalcium and ATX-II

↓ I_Ca-L

In vitro

[39]

Isovitexin

C₂₁H₂₀O₁₀

–

↓ I_Ca-L

In vitro

[40]

Resveratrol

C₁₄H₁₂O₃

VA and AVB following I/R

↓ I_Ca

In vitro

[42, 43]

Orientin

C₂₁H₂₀O₁₁

–

↓ I_Ca-L

In vitro

[44]

Terpenes

Schisandrin B

C₂₃H₂₈O₆

Experimental arrhythmias induced by aconitine

↓ I_Ca-L; ↓ calcium channel, recovery time

In vitro/animal models

[46]

Others

6-Gingerol

C₁₇H₂₆O₄

–

↓ I_Ca-L

In vitro

[47]

Paeonol

C₉H₁₀O₃

–

↓ I_Ca

In vitro

[48]

Crocetin

C₂₀H₂₄O₄

Experimental arrhythmias induced by aconitine, ouabain and calcium chloride

↓ I_Ca

In vitro

[50]

Nardosinone

C₁₅H₂₂O₃

–

↓ I_Ca-L

In vitro

[51]