Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca²⁺ sensitivity of isometric force production (pCa₅₀) and force at low Ca²⁺ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca²⁺ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dt_min) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Omecamtiv mecarbil (OM) 是一种很有前途的改善心肌收缩力的新药。我们测试了 OM 的治疗范围并确定了以前未被识别的副作用。等长力产生 (pCa ₅₀ )的 Ca ²⁺敏感性和低 Ca ²⁺水平的力随着人透化心肌细胞中的 OM 浓度而增加。OM (1 µM) 减缓了收缩和舒张的动力学，并引起正常和减少的细胞内 Ca ^{2+之间的振荡}分离的犬心肌细胞的瞬变、动作电位长度和收缩。超声心动图研究和左心室压力-容积分析表明，大鼠 OM 浓度为 600–1200 µg/kg 时心脏收缩功能的浓度依赖性改善。给予 1200 µg/kg 浓度的 OM 与低血压有关，而 600-1200 µg/kg 的剂量与舒张功能障碍的以下方面有关：E/A 比的降低和舒张压最大下降率（ dP/dt_最小值) 并增加等容舒张时间、左心房直径、等容舒张常数 Tau、左心室舒张末期压力和舒张末期压力-容积关系的斜率。此外，OM 1200 µg/kg 经常在大鼠体内诱发瞬时机电交替，其中正常收缩之后是较小的收缩（和 T 波幅度），而 QRS 复合物没有重大差异。除了改善收缩功能外，OM 还引起舒张功能障碍和交替脉。OM 的狭窄治疗窗口可能需要在临床应用中监测额外的临床安全参数。