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 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 μM). Key Results In permeabilized cardiomyocytes, OM increased the Ca²⁺ sensitivity of force production (ΔpCa₅₀: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca²⁺ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC₅₀: 0.08 ± 0.01 μM). 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 μM. 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.