Ting Chih-Yu, Shih Chia-Lung, Yu Meng-Cheng, Wu Chao-Liang, Wu Sheng-Nan
Department of Emergency Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan.
Clinical Research Center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan.
Biomedicines. 2023 May 3;11(5):1351. doi: 10.3390/biomedicines11051351.
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 GH cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient () and late components () of the voltage-gated Na current () with different potencies in GH cells. The EC value required to observe the stimulatory effect of this compound on or in GH cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of . 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 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 . 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 Ca currents in GH cells. On the other hand, the delayed-rectifier K currents in GH cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of or upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNa1.7 channels. Overall, the direct stimulation of and 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.
奥米卡替麦卡比（OM，CK - 1827452）被认为是肌球蛋白的激活剂，并且已被证明对收缩性心力衰竭的治疗有益。然而，该化合物与电可兴奋细胞中离子电流相互作用的机制在很大程度上仍不清楚。本研究的目的是研究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GH细胞中，全细胞电流记录显示，添加OM对电压门控钠电流（）的瞬态（）和晚期成分（）具有不同的刺激强度。观察到该化合物对GH细胞中或刺激作用所需的EC值分别为15.8和2.3 μM。暴露于OM并不影响的电流 - 电压关系。然而，观察到电流的稳态失活曲线向去极化电位偏移约11 mV，曲线的斜率因子没有变化。添加OM导致在对串脉冲去极化刺激的累积抑制过程中衰减时间常数增加。此外，OM的存在导致在缓慢失活中的恢复时间常数缩短。添加OM还导致由短上升斜坡电压诱发的窗钠电流强度增强。然而，OM暴露对GH细胞中L型钙电流的幅度几乎没有影响。另一方面，观察到GH细胞中的延迟整流钾电流在其存在下受到轻度抑制。Neuro - 2a细胞在添加OM后也显示出对或的差异刺激敏感。分子分析揭示了OM分子与hNa1.7通道之间的潜在相互作用。总体而言，推测OM对和的直接刺激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意义。
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