PDF(Pubmed)
Abstract：
Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.
摘要：
Omecamtivmecarbil(OM,CK-1827452）被认为是肌球蛋白的激活剂，已被证明对治疗收缩性心力衰竭有益。然而,该化合物与可电兴奋细胞中的离子电流相互作用的机制仍然未知。这项研究的目的是研究OM对GH3垂体细胞和Neuro-2a神经母细胞瘤细胞中离子电流的影响。在GH3细胞中，全细胞电流记录显示,添加OM在刺激电压门控Na+电流(INa)的瞬时(INa(T))和晚期分量(INa(L))方面具有不同的效力,在GH3细胞中具有不同的效力.发现观察该化合物对GH3细胞中INa（T）或INa（L）的刺激作用所需的EC50值为15.8和2.3µM，分别。暴露于OM不影响INa(T)的电流与电压的关系。然而,观察到电流的稳态失活曲线向约11mV的去极化电位偏移，曲线的斜率系数没有变化。OM的添加导致响应于脉冲串去极化刺激的INa（T）累积抑制期间衰减时间常数的增加。此外，OM的存在导致INa（T）缓慢失活的恢复时间常数缩短。添加OM还导致窗口Na电流的强度增加，这是由一个短暂的上升斜坡电压引起的。然而,OM暴露对GH3细胞中L型Ca2电流的大小几乎没有影响。另一方面,观察到GH3电池中的延迟整流器K电流在其存在下被轻度抑制。神经-2a细胞在加入OM后也显示出对INa（T）或INa（L）的差异刺激的敏感性。分子分析揭示了OM分子和hNaV1.7通道之间的潜在相互作用。总的来说,OM对INa（T）和INa（L）的直接刺激被认为不是由与肌球蛋白的相互作用介导的，这对其在体内发生的药理或治疗作用具有潜在的影响。
