Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes

Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion...

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Published inJournal of physiology and pharmacology : an official journal of the Polish Physiological Society Vol. 67; no. 4; p. 483
Main Authors Szentandrassy, N, Horvath, B, Vaczi, K, Kistamas, K, Masuda, L, Magyar, J, Banyasz, T, Papp, Z, Nanasi, P P
Format Journal Article
LanguageEnglish
Published Poland 01.08.2016
Subjects
Action Potentials - drug effects
Animals
Dogs
Female
Heart Ventricles - cytology
Male
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - physiology
Myosins
Patch-Clamp Techniques
Urea - analogs & derivatives
Urea - pharmacology
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Summary:Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 μM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 μM; P < 0.05 compared to control). Accordingly, OM (10 μM) decreased the density of the transient outward K current (I ), the L-type Ca current (I ) and the rapid delayed rectifier K current (I ), but failed to modify the inward rectifier K current (I ). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated.
ISSN:1899-1505