Translational Safety & Bioanalytical Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Pharmacol Res Perspect. 2020 Oct;8(5):e00656. doi: 10.1002/prp2.656.
Omecamtiv mecarbil (OM) is a selective cardiac myosin activator (myotrope), currently in Phase 3 clinical investigation as a novel treatment for heart failure with reduced ejection fraction. OM increases cardiac contractility by enhancing interaction between myosin and actin in a calcium-independent fashion. This study aims to characterize the mechanism of action by evaluating its simultaneous effect on myocyte contractility and calcium-transients (CTs) in healthy canine ventricular myocytes. Left ventricular myocytes were isolated from canines and loaded with Fura-2 AM. With an IonOptix system, contractility parameters including amplitude and duration of sarcomere shortening, contraction and relaxation velocity, and resting sarcomere length were measured. CT parameters including amplitude at systole and diastole, velocity at systole and diastole, and duration at 50% from peak were simultaneously measured. OM was tested at 0.03, 0.1, 0.3, 1, and 3 µmol\L concentrations to simulate therapeutic human plasma exposure levels. OM and isoproterenol (ISO) demonstrated differential effects on CTs and myocyte contractility. OM increased contractility mainly by prolonging duration of contraction while ISO increased contractility mainly by augmenting the amplitude of contraction. ISO increased the amplitude and velocity of CT, shortened duration of CT concurrent with increasing myocyte contraction, while OM did not change the amplitude, velocity, and duration of CT up to 1 µmol\L. Decreases in relaxation velocity and increases in duration were present only at 3 µmol\L. In this translational myocyte model study, therapeutically relevant concentrations of OM increased contractility but did not alter intracellular CTs, a mechanism of action distinct from traditional calcitropes.
奥马环素（OM）是一种选择性心肌肌球蛋白激活剂（肌动剂），目前正在进行 III 期临床试验，作为射血分数降低的心力衰竭的新型治疗方法。OM 通过以钙非依赖性方式增强肌球蛋白与肌动蛋白之间的相互作用来增加心肌收缩力。本研究旨在通过评估其对健康犬心室肌细胞的肌细胞收缩力和钙瞬变（CT）的同时作用来表征作用机制。从犬中分离左心室心肌细胞并加载 Fura-2 AM。使用 IonOptix 系统，测量包括肌节缩短幅度和持续时间、收缩和松弛速度以及静息肌节长度在内的收缩性参数。同时测量 CT 参数，包括收缩期和舒张期的幅度、收缩期和舒张期的速度以及从峰值的 50%处的持续时间。以 0.03、0.1、0.3、1 和 3 μmol/L 的浓度测试 OM，以模拟治疗性人体血浆暴露水平。OM 和异丙肾上腺素（ISO）对 CT 和肌细胞收缩力表现出不同的作用。OM 主要通过延长收缩持续时间来增加收缩力，而 ISO 主要通过增加收缩幅度来增加收缩力。ISO 增加 CT 的幅度和速度，同时缩短 CT 的持续时间，伴随着肌细胞收缩的增加，而 OM 直到 1 μmol/L 时才改变 CT 的幅度、速度和持续时间。仅在 3 μmol/L 时观察到舒张速度降低和持续时间增加。在这个转化的肌细胞模型研究中，治疗相关浓度的 OM 增加了收缩力，但没有改变细胞内 CT，这是一种与传统钙调蛋白不同的作用机制。
