Characterization of Stimulatory Action on Voltage-Gated Na(+) Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator

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(3) cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (I(Na(T))) and late components (I(Na(L))) of the voltage-gated Na(+) current (I(Na)) with different potencies in GH(3) cells. The EC(50) value required to observe the stimulatory effect of this compound on I(Na(T)) or I(Na(L)) in GH(3) cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of I(Na(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 I(Na(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 I(Na(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 Ca(2+) currents in GH(3) cells. On the other hand, the delayed-rectifier K(+) currents in GH(3) cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of I(Na(T)) or I(Na(L)) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNa(V)1.7 channels. Overall, the direct stimulation of I(Na(T)) and I(Na(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.