Functional effects of EMD-57033 in isovolumically beating isolated rabbit hearts

The results of isolated myocyte and cardiac muscle experiments indicate that inotropic agents that increase responsiveness of myofilaments to Ca2+ (so-called Ca2+ sensitizers) may prolong myocardial contraction and increase diastolic tone, but the importance of these effects in the whole heart is unclear. Therefore, we studied the effects of the Ca2+ sensitizer EMD-57033 (EMD) on left ventricular (LV) contractile events and passive properties in isovolumically beating isolated rabbit hearts that were buffer perfused at 30 degrees C. Several LV pressure and timing variables were evaluated, including the passive pressure-volume relationship, the Frank-Starling relationship, and the wall stress dependence of the duration of relaxation during perfusion with 0, 2, and 4 mu M EMD. EMD (2 mu M) increased average peak developed pressure of the Frank-Starling relationship by similar to 18%. In contrast, the peak developed pressure of the Frank-Starling relationship decreased toward control with 4 mu M EMD, and therefore all the results presented pertain to 2 mu M EMD. The maximum developed pressure at baseline volume was increased by similar to 19% by 2 mu M EMD, and this was accompanied by an increase in contraction duration of similar to 13%, due exclusively to slowed relaxation. The relative contributions of maximal wall stress (sigma(max)) versus an independent negative lusitropic effect of EMD were determined at three LV volumes. At baseline volume, just less than one-half of the effect to slow relaxation was ascribable to an increase in sigma(max), whereas the remainder was due to an independent EMD effect. LV passive properties were unchanged by perfusion with 2 mu M EMD. We conclude that EMD is a potent inotrope in our isolated rabbit heart preparation, which has no effect on diastolic tone and causes a modest prolongation of contraction duration due to slowed relaxation. At baseline volume, similar to 50% of the slowed relaxation was ascribable to positive inotropy leading to increased sigma(max) whereas the remaining similar to 50% was ascribable to a direct negative lusitropic effect of EMD. We discuss our results in terms of the current hypotheses regarding the mechanism of action of the Ca2+ sensitizers.