Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 22 Móricz Zsigmond Street, 4032, Debrecen, Hungary.
Doctoral School of Kálmán Laki, University of Debrecen, Debrecen, Hungary.
Basic Res Cardiol. 2021 Apr 12;116(1):24. doi: 10.1007/s00395-021-00866-8.
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 Ca sensitivity of isometric force production (pCa) and force at low Ca 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 Ca 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) 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.
奥马环丙基（OM）是一种有前途的改善心肌收缩力的新型药物。我们测试了 OM 的治疗范围，并发现了以前未被识别的副作用。在人类通透心肌细胞中，等长力产生（pCa）和低钙水平下的力对 OM 浓度的依赖性增加。OM（1µM）减缓了收缩和松弛的动力学，并在分离的犬心肌细胞中诱发正常和降低的细胞内 Ca 瞬变、动作电位长度和收缩之间的振荡。超声心动图研究和左心室压力-容积分析表明，在大鼠中，OM 浓度为 600-1200µg/kg 时，心脏收缩功能呈浓度依赖性改善。OM 浓度为 1200µg/kg 时给药与低血压相关，而 600-1200µg/kg 的剂量与舒张功能障碍的以下方面相关：E/A 比值和最大舒张压下降率（dP/dt）降低，等容松弛时间、左心房直径、等容松弛常数 Tau、左心室舒张末期压力和舒张末期压力-容积关系斜率增加。此外，OM 1200µg/kg 经常在体内大鼠中诱发短暂的机电交替，其中正常的收缩之后是较小的收缩（和 T 波幅度），而 QRS 复合体没有明显差异。除了改善收缩功能外，OM 还诱发舒张功能障碍和脉动交替。OM 的治疗窗狭窄可能需要在临床应用中监测其他临床安全参数。
