Similar expression patterns of mRNA profiles for Endothelin 1 (ET-1) and Thrombospondin 1 (TSP1) from GeneAtlas U133A, gcrma, suggest that these two mediators are dominantly synthesized in the myocard and lungs. This paper proposes that intertraffic of these two mediators between myocard and lungs via pulmonary and coronary vessels optimizes cardiopulmonary functions and maintains their tissue integrity. A controlled delivery of endocrine mediators to the left and to the right heart is done by the coronary sinus (CS) that drains venous blood to the right atrium, and Thebesian veins (TVs) that open in all four heart cavities. Myocard and pulmonary capillaries are connected as a bidirectional portal system. Mediators from lungs can directly influence myocardial cells after entering the coronary circulation, while mediators in the myocardial venous blood that drain into the right heart will initially affect lungs. Strain induced myocardial ET-1 secretion into the right heart and pulmonary circulation increases the right heart afterload by constricting pulmonary vasculature. The same action reduces the left heart preload. Pulmonary ET-1 secretion can protect lungs from overperfusion by increasing the left heart afterload through constriction of peripheral arterioles. Chronic tissue overexposure to ET-1 leads to pulmonary and myocardial fibrosis. TSP1 availability is important in tissues under mechanical stress, since TSP1 is an adhesive glycoprotein involved in cell-to-cell and cell-to-matrix interactions. Pulmonary and myocardial TSP1 secretion that enter the fibrillating left atrium can mimic actions of the platelet-derived TSP1 in promoting the thrombus formation.