Jiayu Liang, Xiaofeng Li, Jinhong Chen, Fangjun Deng, Boya Fan, Xin Zhen, Zidong Cong, Rui Tao, Lu Yu, Shule Qian, Runying Wang, Wuxun Du
Department of TCM, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Hangzhou 310003, China.
Department of Cardiology, The Second Affiliated Hospital of Tianjin University of TCM, Tianjin 300150, China.
Heliyon. 2024 Aug 14;10(16):e36104. doi: 10.1016/j.heliyon.2024.e36104. eCollection 2024 Aug 30.
The Chinese herbal compound Lian-Gui-Ning-Xin-Tang (LGNXT), composed of 9 herbs, has a significant antiarrhythmic effect. Previous studies have confirmed that preventing intracellular Ca overload and maintaining intracellular Ca homeostasis may be the important antiarrhythmic mechanisms of LGNXT. Recent studies are focused on elucidating the mechanisms and pharmacodynamic substances of LGNXT.
First, pharmacodynamic studies were conducted to determine the effect of LGNXT in arrhythmia at the electrophysiological, molecular, and tissue levels, and the "effect-time" relationship of LGNXT was further proposed. Next, an HPLC-MS/MS method was established to identify the "dose-time" relationship of the 9 potential compounds. Combining the "effect-time" and "dose-time" curves, the active ingredients closely related to the inhibition of inflammation, oxidative stress, and energy metabolism were identified to further verify the mechanisms and pharmacodynamic substances of LGNXT.
Pretreatment with LGNXT could delay the occurrence of arrhythmias and reduce their duration and severity. LGNXT exerted antiarrhythmic effects by inhibiting MDA, LPO, IL-6, and cAMP; restoring Cx43 coupling function; and upregulating SOD, Ca-ATPase, and Na-K-ATPase levels. PK-PD association showed that nobiletin, methylophiopogonanone A, trigonelline, cinnamic acid, liquiritin, dehydropolisic acid, berberine, and puerarin were the main pharmacodynamic substances responsible for inhibiting the inflammatory response in arrhythmia. Methylophiopogonanone A, dehydropalingic acid, nobiletin, trigonelline, berberine, and puerarin in LGNXT exerted antiarrhythmic effects by inhibiting oxidative stress. Dehydropalingic acid, berberine, cinnamic acid, liquiritin, puerarin, trigonelline, methylophiopogonanone A, nobiletin, and tetrahydropalmatine exerted antiarrhythmic effects by inhibiting the energy-metabolism process.
LGNXT had a positive intervention effect on arrhythmias, especially ventricular tachyarrhythmias, which could inhibit inflammation, oxidative stress, and energy metabolism; positively stabilize the structure, and remodify the function of myocardial cell membranes. Additionally, the PD-PK association study revealed that methylophiopogonanone A, berberine, trigonelline, liquiritin, puerarin, tetrahydropalmatine, nobiletin, dehydropachymic acid, and cinnamic acid directly targeted inflammation, oxidative stress, and energy metabolism, which could be considered the pharmacodynamic substances of LGNXT. Thus, the antiarrhythmic mechanisms of LGNXT were further elucidated.
由9味中药组成的中药复方连归宁心汤（LGNXT）具有显著的抗心律失常作用。既往研究证实，防止细胞内钙超载和维持细胞内钙稳态可能是LGNXT重要的抗心律失常机制。近期研究聚焦于阐明LGNXT的作用机制和药效物质。
1）研究LGNXT的抗心律失常机制；2）探讨LGNXT中潜在药效物质的药效学（PD）与药代动力学（PK）的相关性，进一步验证其作用机制。
首先进行药效学研究，从电生理、分子和组织水平确定LGNXT对心律失常的作用，并进一步提出LGNXT的“效应-时间”关系。其次，建立高效液相色谱-串联质谱（HPLC-MS/MS）方法，确定9种潜在化合物的“剂量-时间”关系。结合“效应-时间”和“剂量-时间”曲线，确定与抑制炎症、氧化应激和能量代谢密切相关的活性成分，进一步验证LGNXT的作用机制和药效物质。
LGNXT预处理可延迟心律失常的发生，降低其持续时间和严重程度。LGNXT通过抑制丙二醛（MDA）、脂质过氧化物（LPO）、白细胞介素-6（IL-6）和环磷酸腺苷（cAMP）发挥抗心律失常作用；恢复连接蛋白43（Cx43）耦联功能；上调超氧化物歧化酶（SOD）、钙-ATP酶和钠-钾-ATP酶水平。PK-PD相关性分析表明，川陈皮素、麦冬甲基黄烷酮A、胡芦巴碱、肉桂酸、甘草苷、脱水茯苓酸、小檗碱和葛根素是LGNXT中抑制心律失常炎症反应的主要药效物质。LGNXT中的麦冬甲基黄烷酮A、脱水茯苓酸、川陈皮素、胡芦巴碱、小檗碱和葛根素通过抑制氧化应激发挥抗心律失常作用。脱水茯苓酸、小檗碱、肉桂酸、甘草苷、葛根素、胡芦巴碱、麦冬甲基黄烷酮A、川陈皮素和延胡索乙素通过抑制能量代谢过程发挥抗心律失常作用。
LGNXT对心律失常尤其是室性快速性心律失常有积极的干预作用，可抑制炎症、氧化应激和能量代谢；积极稳定心肌细胞膜结构，重塑其功能。此外，PD-PK相关性研究表明，麦冬甲基黄烷酮A、小檗碱、胡芦巴碱、甘草苷、葛根素、延胡索乙素、川陈皮素、脱水茯苓酸和肉桂酸直接作用于炎症、氧化应激和能量代谢，可认为是LGNXT的药效物质。由此进一步阐明了LGNXT的抗心律失常机制。
