title: 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: OBJECTIVE
  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.
  
  
  METHODS
  Ca2+-dependent active force production (Factive), its Ca2+sensitivity (pCa50), the kinetic characteristics of Ca2+-regulated activation and relaxation, and Ca2+-independent passive force (Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM).
  
  
  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 Fpassivein the cardiomyocytes with an apparent EC50value 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
  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 Fpassiveproduction.
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Nagy
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Á
authors.initials: Á
authors.lastname: Kovács
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Bódi
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: E T
authors.initials: ET
authors.lastname: Pásztor
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: G Á
authors.initials: GÁ
authors.lastname: Fülöp
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Tóth
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Édes
authors.affiliation: Division of Clinical Physiology, Institute of Cardiology, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Z
authors.initials: Z
authors.lastname: Papp