FUNCTIONAL-EFFECTS OF EMD-57033 IN ISOVOLUMICALLY BEATING ISOLATED RABBIT HEARTS

The results of isolated myocyte and cardiac muscle experiments indicat e that inotropic agents that increase responsiveness of myofilaments t o Ca2+ (so-called Ca2+ sensitizers) may prolong myocardial contraction and increase diastolic tone, but the importance of these effects in t he whole heart is unclear. Therefore, we studied the effects of the Ca 2+ sensitizer EMD-57033 (EMD) on left ventricular (LV) contractile eve nts and passive properties in isovolumically beating isolated rabbit h earts that were buffer perfused at 30 degrees C. Several LV pressure a nd timing variables were evaluated, including the passive pressure-vol ume 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, th e peak developed pressure of the Frank-Starling relationship decreased toward control with 4 mu M EMD, and therefore all the results present ed pertain to 2 mu M EMD. The maximum developed pressure at baseline v olume was increased by similar to 19% by 2 mu M EMD, and this was acco mpanied by an increase in contraction duration of similar to 13%, due exclusively to slowed relaxation. The relative contributions of maxima l wall stress (sigma(max)) versus an independent negative lusitropic e ffect of EMD were determined at three LV volumes. At baseline volume, just less than one-half of the effect to slow relaxation was ascribabl e to an increase in sigma(max), whereas the remainder was due to an in dependent EMD effect. LV passive properties were unchanged by perfusio n with 2 mu M EMD. We conclude that EMD is a potent inotrope in our is olated rabbit heart preparation, which has no effect on diastolic tone and causes a modest prolongation of contraction duration due to slowe d relaxation. At baseline volume, similar to 50% of the slowed relaxat ion was ascribable to positive inotropy leading to increased sigma(max ) whereas the remaining similar to 50% was ascribable to a direct nega tive lusitropic effect of EMD. We discuss our results in terms of the current hypotheses regarding the mechanism of action of the Ca2+ sensi tizers.