Endocardial and coronary vascular endothelial cells release substances that modify the contraction of cardiac myocytes. The major and possibly the sole up-regulating substance is endothelin. Several down-regulating substances are secreted, but none has yet been specifically identified. The relative amounts of up- and down-regulating substances are related to tissue oxygen tension. As pO2 rises, the concentration of up- and down-regulating substances, respectively, increases and decreases. Endothelin increases isometric force and decreases actomyosin ATPase activity thus increasing the economy of conversion of chemical to hydrodynamic energy. Beta-adrenergic agonists increase ATPase activity through an endothelial cell-dependent mechanism, leading to decreased economy. Therefore, two endothelial cell-dependent systems exist for regulating contractile efficiency: One involving endothelin appears to optimize the contraction for efficiency; the other, the beta-adrenergic-mediated system, optimizes for power.