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 mu mol/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 mu mol/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 mu mol/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.

Automated summary

The cardiac-specific myosin activator omecamtiv mecarbil has differential effects on active force and Ca2+ kinetics in healthy and diseased myocardium, with the higher concentration showing significant suppression of active tension-length relationships in healthy rats but not in rats with heart failure. This suggests that the drug may have different impacts on cardiac function depending on the underlying health of the myocardium.