人类和狗心室肌细胞原代肌节缩短和钙瞬变的评估。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2023-09-01 DOI:10.1016/j.vascn.2023.107278
BaoXi Gao , Najah Abi-Gerges , Ky Truong , Alexa Stafford , William Nguyen , Weston Sutherland , Hugo M. Vargas , Yusheng Qu
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引用次数: 1

摘要

了解从临床前观察到临床结果的转化对于评估新化合物的有效性和安全性非常重要。与心脏安全相关的是分析药物对心肌细胞(CM)肌节缩短和细胞内Ca2+动力学的影响。尽管来自不同动物物种的CM已被用于评估这种影响,但从人类器官供体心脏中分离的原始人类CM代表了一种理想的非动物替代方法。我们进行了一项研究来评估原发人心肌细胞,并将其与新鲜分离的狗心肌细胞进行比较,以了解其基本功能和对正性肌力的反应。我们的数据表明,使用IonOptix系统可以同时评估肌节缩短和Ca2+瞬态。在基本条件下(未治疗),狗的肌节缩短幅度和Ca2+-transient (CaT)明显高于人的CM,而在人细胞中观察到肌节缩短和CaT的持续时间更长。我们观察到人类和狗的CMs对五种机制不同的肌力药物有相似的药理反应,包括多巴酚丁胺和异丙肾上腺素(β-肾上腺素能刺激),米力酮(PDE3抑制),匹莫苯丹和左西孟丹(增加Ca2+敏化和PDE3抑制)。总之,我们的研究表明,通过IonOptix平台,从人类供体心脏和狗的心脏中获得的肌细胞可以同时用于评估药物对肌节缩短和CaT的影响。
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Assessment of sarcomere shortening and calcium transient in primary human and dog ventricular myocytes

Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca2+ dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ donor heart represent an ideal non-animal alternative approach. We performed a study to evaluate primary human CM and have them compared to freshly isolated dog cardiomyocytes for their basic function and responses to positive inotropes with well-known mechanisms. Our data showed that simultaneous assessment of sarcomere shortening and Ca2+-transient can be performed with both myocytes using the IonOptix system. Amplitude of sarcomere shortening and Ca2+-transient (CaT) were significantly higher in dog compared to human CM in the basic condition (absence of treatment), while longer duration of sarcomere shortening and CaT were observed in human cells. We observed that human and dog CMs have similar pharmacological responses to five inotropes with different mechanisms, including dobutamine and isoproterenol (β-adrenergic stimulation), milrinone (PDE3 inhibition), pimobendan and levosimendan (increase of Ca2+sensitization as well as PDE3 inhibition). In conclusion, our study suggests that myocytes obtained from both human donor hearts and dog hearts can be used to simultaneously assess drug-induced effects on sarcomere shortening and CaT using the IonOptix platform.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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