A system for regulating cardiac contractility in addition to the Frank Starling pressure-volume relation and neuroendocrine control has recently been identified. The major function of this system appears to be coordination of the contractility and the rate of coronary blood flow to maintain a proper balance between work performed by cardiac myocytes and energy and oxygen supplied to the myocytes. Such a balance is crucial for the viability and adaptability of the heart. Highly specific intercellular signaling between cardiac myocytes and vascular endothelial cells provides the necessary information flow for the regulation. Tissue oxygen tension is the key indicator of oxygen supply and use, and endothelin is an important modulator of contractile force of both cardiac and vascular smooth muscle myocytes. A peptide coordinates the response of cardiac and vascular myocytes to endothelin. This peptide, secreted by cardiac myocytes in accordance with tissue p02, appears to modulate the secretion of endothelin by endothelial cells. The rate of synthesis of endothelin by vascular endothelial cells is sensitive to coronary blood flow presumably through the shear force generated on the endothelial cells.