Dataset Information

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

ABSTRACT:

Background and purpose

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions.

Experimental approaches

Ca²⁺ -dependent active force production (F_active ), its Ca²⁺ sensitivity (pCa₅₀ ), the kinetic characteristics of Ca²⁺ -regulated activation and relaxation, and Ca²⁺ -independent passive force (F_passive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 ?M).

Key results

In permeabilized cardiomyocytes, OM increased the Ca²⁺ sensitivity of force production (?pCa₅₀ : 0.11 or 0.34 at 0.1 or 1??M respectively). The concentration-response relationship of the Ca²⁺ sensitization was bell-shaped, with maximal effects at 0.3-1??M OM (EC₅₀ : 0.08 ± 0.01??M). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased F_passive in the cardiomyocytes with an apparent EC₅₀ value of 0.26 ± 0.11??M. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics.

Conclusions and implications

OM acted as a Ca²⁺ -sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased F_passive production.

SUBMITTER: Nagy L

PROVIDER: S-EPMC4562511 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

Nagy L L Kovács Á Á Bódi B B Pásztor E T ET Fülöp G Á GÁ Tóth A A Édes I I Papp Z Z

British journal of pharmacology 20150804 18

<h4>Background and purpose</h4>Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions.<h4>Experimental approaches</h4>Ca<sup>2+</sup> -dependent active force production (F<sub>active</sub> ), its Ca<sup>2+</sup> sensitivity (pCa<sub>5 ...[more]

PMID: 26140433

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Project description: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.

Dataset Information

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

Background and purpose

Experimental approaches

Key results

Conclusions and implications

Publications

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

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