The energy-saving effect of a new myosin activator, omecamtiv mecarbil, on LV mechanoenergetics in rat hearts with blood-perfused isovolumic contraction model
The energy-saving effect of a new myosin activator, omecamtiv mecarbil, on LV mechanoenergetics in rat hearts with blood-perfused isovolumic contraction model
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DOI：
10.1007/s00210-019-01685-4
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发表时间：
2019-07
期刊：
影响因子：
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通讯作者：
K. Obata;H. Morita;M. Takaki
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文献类型：
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作者：
K. Obata;H. Morita;M. Takaki
一种新型肌球蛋白激活剂Omecamtiv Mecarbil（OM）是一种具有独特新作用机制的心脏变力剂，其作用机制被认为是肌球蛋白向肌动蛋白结合力产生状态的转变速率增加，而不增加钙（Ca 2+）瞬变。然而，OM对心肌收缩力和能量消耗的影响仍存在相当大的争议。在本研究中，我们研究了OM对左心室（LV）机械功和能量学的影响，即，在大鼠正常心脏（CTL）和慢性给予异丙肾上腺素（1.2 mg/kg/天）4周诱导的衰竭心脏（ISO-HF）中的机械能学。我们分析了左室收缩末期压力-容积关系（ESPVR）和心肌耗氧量（VO 2）和收缩压-容积面积（PVA;每拍的总机械能）之间的线性关系，在等容收缩大鼠心脏在240或300 bpm起搏在没有或存在OM。OM没有改变CTL和ISO-HF的ESPVR。OM显著降低CTL和ISO-HF的VO 2-PVA关系的斜率，显著增加ISO-HF的平均VO 2截距，而不改变基础代谢。这些结果表明，OM提高了PVA的氧消耗（收缩效率），而在CTL和ISO-HF中的LV收缩性不变，但在ISO-HF中增加了用于兴奋-收缩（E-C）偶联（E-C）中Ca 2+处理的VO 2。我们的结论是，OM提高收缩效率在正常和衰竭的心脏，但增加O2消耗的Ca 2+处理在衰竭的心脏在等容收缩大鼠模型。
A novel myosin activator, omecamtiv mecarbil (OM), is a cardiac inotropic agent with a unique new mechanism of action, which is thought to arise from an increase in the transition rate of myosin into the actin-bound force-generating state without increasing calcium (Ca2+) transient. There remains, however, considerable controversy about the effects of OM on cardiac contractility and energy expenditure. In the present study, we investigated the effects of OM on left ventricular (LV) mechanical work and energetics, i.e., mechanoenergetics in rat normal hearts (CTL) and failing hearts induced by chronic administration of isoproterenol (1.2 mg/kg/day) for 4 weeks (ISO-HF). We analyzed the LV end-systolic pressure-volume relation (ESPVR) and the linear relation between the myocardial oxygen consumption per beat (VO2) and systolic pressure-volume area (PVA; a total mechanical energy per beat) in isovolumically contracting rat hearts at 240- or 300-bpm pacing in the absence or presence of OM. OM did not change the ESPVR in CTL and ISO-HF. OM, however, significantly decreased the slope of VO2–PVA relationship in both CTL and ISO-HF, and significantly increased the mean VO2intercept without changes in basal metabolism in ISO-HF. These results suggested that OM improved the oxygen cost of PVA (contractile efficiency) with the unchanged LV contractility in both CTL and ISO-HF but increased VO2for Ca2+handling in excitation–contraction (E–C) coupling in ISO-HF. We concluded that OM improves contractile efficiency in normal and failing hearts but increases O2consumption of Ca2+handling in failing hearts in isovolumically contracting rat model.