Frequency-dependent effects of omecamtiv mecarbil on cell shortening of isolated canine ventricular cardiomyocytes

Abstract

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 Ca ([Ca]) 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 [Ca] were followed using the Ca-sensitive dye Fura-2. At the pacing frequency of 1 Hz, OM (1-10 μM) significantly decreased both diastolic and systolic cell length, however, fractional shortening was augmented only by 1 μM 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 μM 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 [Ca] 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.

A microwell cell capture device reveals variable response to dobutamine in isolated cardiomyocytes

“…5) and suggests the presence of substantial noise in the expression of genes that participate in the β-adrenergic signaling pathway. Cardiomyocyte responses to OM were consistent with other recent reports (3,7), including the observation that OM increases contractility at the expense of diastolic function.…”

Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results

“…Similar effects were obtained under in vivo conditions in anesthetized dogs and rats, where omecamtiv mecarbil displayed more pronounced action in the canine hearts [22]. However, the effects of omecamtiv mecarbil on cell shortening are concentration-and frequency-dependent in canine ventricular cells [40]. As demonstrated in Fig.…”

Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke

“…Biochemical kinetic experiments have suggested that OM does not affect the actomyosin-detachment rate during cycling 1 , 6 , which is at odds with our findings. However, studies of tension development and relaxation rates of cardiac muscle preparations have indicated that detachment may be slowed by OM 11 , 12 , 34 . The previous biochemical conclusions 1 , 6 were based on the measurement of the rate of ADP release (the step that limits the rate of actin detachment at physiological ATP) from an AM·ADP complex formed by adding ADP to the rigor, AM complex in isolated actomyosin 1 , 6 , 9 Our results indicate that the step that limits actin detachment is not accessible by simply adding ADP, but occurs earlier in the cycle and may not be on the conventional ATPase pathway (Fig.…”