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Frequency-dependent effects of omecamtiv mecarbil on cell shortening of isolated canine ventricular cardiomyocytes

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Abstract

Omecamtiv mecarbil (OM) is a myosin activator agent developed for the treatment of heart failure. OM was reported to increase left ventricular ejection fraction and systolic ejection time, but little is known about the effect of heart rate on the action of OM. The present study, therefore, was designed to investigate the effects of OM on unloaded cell shortening and intracellular Ca2+ ([Ca2+]i) transients as a function of the pacing frequency. Isolated cardiomyocytes were stimulated at various frequencies under steady-state conditions. Cell length was monitored by an optical edge detector and changes in [Ca2+]i were followed using the Ca2+-sensitive dye Fura-2. At the pacing frequency of 1 Hz, OM (1–10 μM) significantly decreased both diastolic and systolic cell length, however, fractional shortening was augmented only by 1 μM OM. Time to peak tension and time of 90% relaxation were progressively increased by OM. At the frequency of 2 Hz, diastolic cell length was reduced by 10 μM OM to a larger extent than systolic cell length, resulting in a significantly decreased fractional shortening under these conditions. OM had no effect on the parameters of the [Ca2+]i transient at any pacing frequency. The results suggest that supratherapeutic concentrations of OM may decrease rather than increase the force of cardiac contraction especially in tachycardic patients.

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Acknowledgements

The authors thank Miss Éva Sági for excellent technical assistance.

Funding

Financial support was provided by grants from the National Research Development and Innovation Office, NKFIH (K115397, K109736, K101196, and PD120794), from the University of Debrecen (RH/751/2015), and János Bolyai Research Scholarship of the Hungarian Academy of Sciences for NS and BH. The publication is supported also by the GINOP-2.3.2-15-2016-00040 project, which was co-financed by the European Union and the European Regional Development Fund.

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Author notes

  1. Balázs Horváth and Norbert Szentandrássy have equally contributed.

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, Debrecen, 4012, Hungary

    Balázs Horváth, Norbert Szentandrássy, Roland Veress, János Almássy, János Magyar, Tamás Bányász & Péter P. Nánási

  2. Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary

    Balázs Horváth

  3. Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary

    Norbert Szentandrássy & Péter P. Nánási

  4. Division of Sport Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    János Magyar

  5. Division of Clinical Physiology, Department of Cardiology, Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Attila Tóth & Zoltán Papp

Authors
  1. Balázs Horváth
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  9. Péter P. Nánási
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Correspondence to Péter P. Nánási.

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The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. The experiments were performed according to protocols approved by the local ethical committee (license no. 18/2012/DEMÁB).

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Horváth, B., Szentandrássy, N., Veress, R. et al. Frequency-dependent effects of omecamtiv mecarbil on cell shortening of isolated canine ventricular cardiomyocytes. Naunyn-Schmiedeberg's Arch Pharmacol 390, 1239–1246 (2017). https://doi.org/10.1007/s00210-017-1422-z

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  • DOI: https://doi.org/10.1007/s00210-017-1422-z

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