Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action.
Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action.
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Enzastaurin 心脏毒性：QT 间期延长、负性肌力反应和负性变时作用。
DOI：
10.1016/j.bcp.2023.115443
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发表时间：
2023
影响因子：
5.8
通讯作者：
Yanhui Zhang
中科院分区：
文献类型：
--
作者：
Heng Zhang;Jianghua Lin;Lei Pan;Liang Mao;Jingtuan Pang;Qian;Gui;Gang;Yang Lin;Bao;Yun;Yan Wang;Ling Jie;Yanhui Zhang
多项临床试验观察到，苯扎托林延长了癌症患者的QT间期。然而，苯扎托林引起QT间期延长的机制尚不清楚。因此，本研究旨在探讨左旋糖苷对QT间期和心功能的影响及其作用机制。用Langdorff和Ion-Optix MyoCam系统观察了恩扎司他林对豚鼠心脏和心室肌细胞QT间期、心脏收缩功能和细胞内钙瞬变的影响。采用全细胞记录技术和Western blotting技术，观察了恩施他林对HEK 2 93细胞和原代培养心肌细胞的快速延迟整流钾电流(IKR)、慢延迟整流钾电流(IKs)、瞬时外向钾电流(ITO)、动作电位、RyR2受体(RyR2)和肌浆/内质网钙ATPase 2a(SERCA2a)表达和活性的影响。结果表明，苯扎托林可剂量依赖性地延长豚鼠心脏QT间期，延长豚鼠心肌细胞动作电位时程。在开放和关闭状态下，enzastaurin均通过与人的Ether-ka-Go-Go相关基因(HERG)通道结合而有效地抑制IKr，而HERG突变通道，包括S636A、S631A和F656V，减弱了enzastaurin的抑制作用。恩扎司他林也适度降低了IKs。此外，苯扎托林还具有负性变时性作用。此外，Zenzastaurin通过抑制RyR2的磷酸化，损害心脏收缩功能，减少细胞内钙瞬变。综上所述，我们发现，苯扎托林延长QT，减慢心率，损害心脏收缩功能。因此，我们建议在给癌症患者用药时，应持续监测心电图和心功能。
Several clinical trials observed that enzastaurin prolonged QT interval in cancer patients. However, the mechanism of enzastaurin-induced QT interval prolongation is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (IKr), the slow delayed rectifier K+current (IKs), transient outward potassium current (Ito), action potentials, Ryanodine Receptor 2 (RyR2) and the sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibitedIKrby binding to the human Ether-à-go-go-Related gene (hERG) channel in both open and closed states, and hERG mutant channels, including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreasedIKs. Additionally, enzastaurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is administered to cancer patients.
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影响因子：
64.5
作者：
Wang W;MacKinnon R
通讯作者：
MacKinnon R
DOI：
--
发表时间：
1994-04
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
M. Slawsky;N. Castle
通讯作者：
M. Slawsky;N. Castle
enzastaurin 在难治性原发性中枢神经系统肿瘤儿科患者中的 1 期和药代动力学研究：一项儿科脑肿瘤联合研究。
影响因子：
15.9
作者：
Kilburn,LindsayB;Kocak,Mehmet;Decker,RodneyL;Wetmore,Cynthia;Chintagumpala,Murali;Su,Jack;Goldman,Stewart;Banerjee,Anuradha;Gilbertson,Richard;Fouladi,Maryam;Kun,Larry;Boyett,JamesM;Blaney,SusanM
通讯作者：
Blaney,SusanM
过度表达 SR CaATPase 的小鼠心室肌细胞的肌浆网功能。
DOI：
10.1006/jmcc.1998.0834
发表时间：
1998
期刊：
Journal of molecular and cellular cardiology.
影响因子：
--
作者：
Yao,A;Su,Z;Dillmann,WH;Barry,WH
通讯作者：
Barry,WH
影响因子：
3.6
作者：
Kamiya, K;Mitcheson, JS;Sanguinetti, MC
通讯作者：
Sanguinetti, MC