Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity.

A ctivation of endothelial cells by physical, chemical , and hormonal stimuli can result in the release of a number of vasoactive mediators.1 Under physiological conditions, mediator release appears to be balanced in favor of inhibitory factors such as endothelium-derived relaxing factor (EDRF, identified as nitric oxide) and prostacyclin (PGI2) (Figure 1).'-3 EDRF-NO and PGI have important protective actions in the vascular wall: They are potent inhibitors of smooth muscle contraction and smooth muscle proliferation,14 and they also inhibit platelet aggregation, stimulate platelet disaggregation, and inhibit platelet or monocyte adhesion to the endothelial surface.25,6 The endothelial cells located at sites that are prone to atherosclerosis appear to be morphologically and functionally different from normal endothelial cells.7-10 These endothelial cells have a diminished protective role in the blood vessel wall and may actively promote the atherosclerotic process.8 Numerous studies have demonstrated that a dysfunction in the release of EDRF-NO appears to occur at an early stage in the atherosclerotic process in animals and humans .'1-23 This impairment in EDRF-NO release may be associated with an increased release of endothelium-derived contracting factors (EDCFs),18'24 which are functional and chemical antagonists of EDRF-NO' 25-29 (Figure 1). The shift in the balance of endothelial mediators might contribute in part to the diminution in the protective role of the endothelium and could predispose the blood vessel to vasospasm or to a further progression of the disease process. Previous studies have demonstrated that the impairment in endothelial dilator activity that occurs in ath-erosclerotic or hypercholesterolemic blood vessels reflects an impairment in the ability of the cells to respond to specific stimuli. Thus, in a number of different arterial preparations (Table 1), hypercholesterolemia did not affect the endothelium-dependent relaxations evoked by certain stimuli, e.g., A23187, but caused The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. marked impairment of responses evoked by other ago-nists, e.g., serotonin or acetylcholine17-19'21-23,30 (Table 1). The endothelium-dependent relaxation evoked by each of the stimuli, whether or not they were impaired during hypercholesterolemia, appears to be mediated by EDRF-NO. For example, in rabbit aorta, the endothe-lium-dependent relaxations evoked by A23187 or ace-tylcholine were unaffected by inhibition of cyclooxygen-ase but were both highly sensitive to inhibition by hemoglobin, which binds EDRF-NO; by methylene blue, which inhibits guanyl cyclase; or by L-arginine analogues, which inhibit the synthesis of EDRF-NO.30,31 The endothelium-dependent relaxations evoked by ace-tylcholine and …