Characterisation of the cardiac electrophysiological actions of omecamtiv mecarbil

Left ventricular systolic heart failure is associated with decrease in myocardial contractility. Omecamtiv mecarbil (OM) is a cardiac-specific myosin activator, which is being studied for a potential role in the treatment of systolic heart failure. By activating myocardial myosin ATPase and increasing the rate of phosphate release from myosin, OM increases left ventricular muscle contractility, thus stroke volume, and systolic ejection time without increasing calcium concentration in the cell, in other words the oxygen consumption.
The aim of this study was to investigate the electrophysiological effects of OM in mammalian myocardium. Whole-cell voltage-clamp and sharp microelectrode techniques were used to measure ion currents and action potential (AP), respectively. All experiments were carried out on enzymatically isolated canine left ventricular cells at 37 °C. Data is given as average±SEM and statistical significance was tested by paired Student’s t-test.
Action potential duration at 90 % repolarization (APD90) was reduced in 10 microM of OM by 10.0±4.0 ms. Early repolarization of AP decreased to 82.6±3.4 % in the presence of 10 microM OM, whereas the plateau potential at half APD90 was decreased by 2.9±1.6 mV. 10 microM OM induced a 10.9±1.4 % reduction of inward rectifier potassium current, 25.8±3.8 % reduction of transient outward potassium current, 18.0±3.7 % reduction of the rapid component of delayed rectifier potassium current and 30.2±9.1 % reduction of L-type calcium current. These actions of OM were statistically significant tested by paired Student’s t-test but hardly reversible upon washout of the drug.
Our results indicate that the reduction of the examined ion currents could explain the actions of OM on the contour of the AP. These findings would question the potential therapeutic application of OM due to a possible harmful electrophysiological side-effect. One must keep in mind, however, that the therapeutic concentration of OM would probably not even reach 1 microM.