T HE VASCULAR endothelium lining as a monolayer the entire circulatory system does not represent a passive diffusion barrier but displays the features of a distributed organ (1 to 1.5 kg) with a variety of biological functions. It serves as an antithrombogenic surface, and it is significantly involved in a well-regulated balance between coagulation and fibrinolysis. To this end its surface contains heparan sulfate and it is able to secrete antithrombin III, prostacyclin, and plasminogen activator. In combination with the negative surface charges of the endothelial glycocalyx, these compounds maintain the fluidity of the blood at the interface between the streaming blood and the vessel wall and prevent red cells from adhering. A number of compounds are synthesized by the endothelium, which may be involved in localized thrombus formation (Table 1). Other important functions comprise the metabolism of norepinephrine (NE), serotonin (5-HT), and adenine nucleotides and the conversion of angiotensin I and bradykinin (Bk) by angiotensin-converting enzyme and other peptidases (Table 2). (See Endothelial Metabolism and its Influence on Vascular Tone.) In spite of the fact that endothelial cells display such a variety of synthetic, secretory, and cleavage functions,’ it was not recognized until 1980 when Furchgott and Zawadzki* made pioneering observations as to how the endothelium exerts a significant role in the modulation of local vascular tone by the release of an endotheliumderived vascular relaxant factor (EDRF) (for recent reviews see references 3 through 7; see also Addendum). In this review we try to summarize recent findings regarding the regulatory function of this endothelium-derived relaxant factor under physiologic and pathophysiologic conditions. In addition, some biochemical properties of endothelial cells that may influence vascular homeostasis and vascular tone are briefly outlined. This role of the endothelium may be especially important in pathophysiologic conditions, when endothelial function is impaired (eg, under arteriosclerotic conditions and during hypercholesterolemia) and its local dilator potential is either reduced or absent. Under such conditions the net balance between dilatory signals from the endothelium, acting indirectly, and direct constrictor impulses affecting the vasculature is disturbed: failure of vasodilation may result in enhanced or excessive local vasoconstriction and spasm, and thus partial or complete ischemia. The decisive role of such an endotheliumdependent vasomotor balance becomes obvious when one considers that the majority of vasoactive agonists (such as [5-HT], histamine, adenosine diphosphate [ADP], adenosine triphosphate [ATP], acetylcholine (ACh), thrombin [Th], vasopressin) display an endothelium-dependent vasodilator activity in addition to a simultaneous direct constrictor effect on vascular smooth muscle. In this context it is surprising that various a-agonists or substances stimulating a-receptors (eg, NE and various ergot alkaloids like ergonovine, which are used to provoke spasm in Prinzmetal patients) exhibit a simultaneous endothelium-dependent dilator component. Consequently, the resultant action on the coronary arterial wall depends on the balance of these two opposing actions (Table 3). EDRF-mediated modulation of vascular tone has been primarily demonstrated in large conductance arteries like the coronaries’ (for review see reference 6), wherein vasomotion does not determine the rate of tissue perfusion unless critical stenoses are present. The role of EDRFmediated vasomotion in resistance vessels, which are responsible for control of tissue perfusion, has not yet been well established, because of difficulties in functionally inhibiting or destroying the endothelium in a defined manner without causing simultaneous damage to the adjacent tissue. The problems caused by increasing overlap with concurrent metabolically induced vasomotion in the microcirculation renders such a quantitative