Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume 390, Issue 12, Pages 1239-1246Publisher
SPRINGER
DOI: 10.1007/s00210-017-1422-z
Keywords
Cardiac myocytes; Cell shortening; Cytosolic Ca2+; Myosin activators; Omecamtiv mecarbil
Categories
Funding
- National Research Development and Innovation Office, NKFIH [K115397, K109736, K101196, PD120794]
- University of Debrecen [RH/751/2015]
- Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences
- European Union
- European Regional Development Fund
- [GINOP-2.3.2-15-2016-00040]
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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 mu M) significantly decreased both diastolic and systolic cell length, however, fractional shortening was augmented only by 1 mu M 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 mu M 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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