Omecamtiv mecarbil attenuates length-tension relationship in healthy rat myocardium and preserves it in monocrotaline-induced pulmonary heart failure.

The cardiac-specific myosin activator, omecamtiv mecarbil (OM), is an effective inotrope for treating heart failure but its effects on active force and Ca2+ kinetics in healthy and diseased myocardium remain poorly studied. We tested the effect of two concentrations of OM (0.2 and 1 µmol/L in saline) on isometric contraction and Ca-transient (CaT) in right ventricular trabeculae of healthy rats (CONT, n = 8) and rats with monocrotaline-induced pulmonary heart failure (MCT, n = 8). The contractions were obtained under preload of 75%-100% of optimal length (tension-length relationship). The 0.2 µmol/L OM did not affect the diastolic level, amplitude, or kinetics of isometric contraction and CaT, irrespective of the group of rats or preload. The 1 µmol/L OM significantly suppressed active tension-length relationships in CONT but not in MCT, while leading in both groups to a significantly prolonged relaxation. CaT time-to-peak was unaffected in CONT and MCT, but CaT decay was slightly accelerated in its early phase and considerably prolonged in its late phase to a similar extent in both groups. We conclude that the substantial prolongation of CaT decay is due to enhanced Ca2+ utilisation by troponin C mediated by the direct effect of OM on the cooperative activation of myofilaments. The lack of beneficial effect of OM in the healthy rat myocardium may be due to a relatively high level of activating Ca2+ in cells with normal Ca2+ handling, whereas the preservation of the tension-length relationship in the failing heart may relate to the diminished Ca2+ levels of sarcoplasmic reticulum.