An increase in the responsiveness of the contractile machinery to Ca²⁺ could theoretically enhance the mechanoenergetics of the heart. To clarify this unresolved issue, we studied the effects of MCI-154, a Ca²⁺ sensitizer, on the mechanoenergetics in terms of the left ventricular contractility index [slope of end-systolic pressure-volume relationship (E_max)] and the relationship between myocardial oxygen consumption (VO₂) and left ventricular pressure-volume area in excised cross-circulated canine hearts. MCI-154 increased E_max by 42 ± 31% (SD), although the slope of the VO₂-PVA relationship (an indicator of contractile efficiency) was unchanged by MCI-154. Despite equal increases in E_max, the relative increase in unloaded VO₂ (VO₂/E_max) during infusion of MCI-154 was, however, significantly less than that during CaCl₂ infusion (0.0016 ± 0.0018 vs. 0.0059 ± 0.0054; P < 0.05). By contrast, VO₂/E_max for milrinone was the same as that for CaCl₂ (0.0043 ± 0.0041 vs. 0.0039 ± 0.0045; P > 0.05). Basal metabolism in KCl-arrested hearts was unchanged by MCI-154, indicating that MCI-154 consumes less energy than CaCl₂ for excitation-contraction coupling. These findings suggest that MCI-154 acts energetically as a Ca²⁺ sensitizer in beating canine whole hearts.