CARDIAC ENDOTHELIAL-CELLS MODULATE CONTRACTILITY OF RAT-HEART IN RESPONSE TO OXYGEN-TENSION AND CORONARY FLOW

The aim of this study was to determine if endothelial cells in the hea rt release substances into the coronary perfusion medium that modify t he contractility of myocardial cells. To assay the effects on the cont ractility of cardiac muscle of fluid that has passed through the coron ary vasculature, a new method has been developed based on the cascade principle used to study vascular smooth muscle function. The coronary venous effluent from an isolated perfused working heart was collected periodically, and after reoxygenation it was used as the bathing mediu m for trabeculae isolated from the endocardial surface of another hear t. The coronary venous effluent changed the contraction of the isolate d trabeculae. The amplitude and the direction of the change depended o n the degree of oxygen saturation of the coronary effluent before it w as reoxygenated and the rate of coronary flow at the time the effluent was collected. The response of the trabecula to the coronary effluent was substantially altered by damaging the endocardial endothelium wit h a 1-second exposure to 0.5% Triton X-100 in Krebs' solution. It was completely eliminated by damaging endothelial cells in both the perfus ed heart producing the effluent and the trabecula on which the effluen t was assayed. Therefore, endothelial cells are required for the prese nce of cardioactive substances in the coronary effluent. The productio n of a labile endothelium-derived upregulating (positively inotropic) factor and a more stable endothelium-derived downregulating (negativel y inotropic) factor has been demonstrated and appears to account for a ll of the changes in myocardial contractility produced by the coronary effluent. Neither of the endothelium-derived substances demonstrated in the isolated perfused heart is nitric oxide or endothelin. The conc entration of the endothelium-derived upregulating factor is sensitive to oxygen tension, whereas the concentration of the endothelium-derive d downregulating factor is sensitive to the rate of coronary flow but not oxygen tension. The coronary effluent appears to contain substance s that stimulate secretion by the endothelial cells (preendothelial fa ctors) as well as substances that have been produced by the endothelia l cells (endothelial factors). The results indicate that during the pa ssage of perfusion medium through the coronary vasculature upregulatin g and downregulating factors are added to the perfusate in relative co ncentrations that depend at least in part on local tissue PO2 and the rate of coronary flow. In the intact heart, this mechanism could opera te to maintain balance between energy supply and work performed.