Cardioprotective Properties of Omecamtiv Mecarbil against Ischemia and Reperfusion Injury.

ABSTRACT

Omecamtiv mecarbil (OM) is a first-in-class myosin activator. It was developed as a new inotropic therapy option for heart failure and is currently the object of a phase 3 clinical trial program. OM activates ryanodine receptors, which were shown to be involved in cardioprotection induced by conditioning strategies. We hypothesize that OM exerts a concentration-dependent cardioprotective effect through pre- and postconditioning. Isolated male Wistar rat hearts underwent 33 min of global ischemia and 60 min of reperfusion. OM was administered in various concentrations (1, 3, 10, and 30 µM) over 10 min prior to ischemia. Based on these results, in subsequent experiments 3 and 10 µM OM were given over 10 min after ischemia. Infarct sizes were determined by TTC staining. In controls, the infarct size was 60% ± 10% and 59% ± 12%, respectively. Ten micromolar OM before ischemia reduced the infarct size to 33% ± 8%. The lower concentrations did not initiate cardioprotection, and the next highest concentration did not enhance the protective effect. Even if 10 µM OM was given in the early reperfusion phase, it significantly reduced the infarct size (31% ± 6%), whereas 3 µM OM did not trigger a protective effect (58% ± 15%). This study shows for the first time that OM induces cardioprotection by pre- and postconditioning with a binary phenomenon, which is either ineffective or has a maximal effect.