Testing endothelial vasomotor function: nitric oxide, a multipotent molecule.

Abstract

The initial description in 1980 by Furchgott and Zawadzki1 of endothelium-derived vasodilator factor has stimulated more than 2 decades of intense research to delineate the basic biology of the endothelium and its importance in the clinical setting.2 Endothelium-derived vasodilator factor has been identified as nitric oxide (NO).2 It is formed in endothelial cells from the amino acid l-arginine by endothelial isoform of NO synthase (eNOS), which is the product of the NOS3 gene.2,3 In addition to producing NO constitutively, the enzyme may be stimulated to increase NO synthesis by a variety of physiological agonists, shear stress, and pharmacological agents. Although discovered as a vasodilator, NO mediates many of the protective functions of the endothelium.4 It limits vascular recruitment of leukocytes by inhibiting the expression of proinflammatory cytokines, chemokines, and leukocyte adhesion molecules.2,4 It inhibits vascular smooth muscle proliferation and platelet adhesion and aggregation.2,4 NO also inhibits the production of tissue factor, a molecule that plays a critical role in the propensity of disrupted atherosclerotic plaques to cause intravascular thrombosis.5 In the setting of risk factors and experimental atherosclerosis, loss of the biological activity of endothelium-derived NO is accompanied by other alterations in endothelial phenotype that further increase the propensity for vasoconstriction, thrombosis, inflammation, and cellular proliferation in the vascular wall.6 Thus, endothelial dysfunction has the potential to contribute to key events in the course of human atherosclerosis. The experimental observations of Furchgott and others have stimulated translational research to elucidate the importance of endothelium-dependent vasodilation in human coronary atherosclerosis. Accordingly, Ludmer and colleagues7 administered the endothelium-dependent dilator acetylcholine into the coronary arteries of subjects undergoing cardiac catheterization. Acetylcholine induced dilation of normal epicardial coronary arteries but induced abnormal vasoconstriction, indicative of endothelial dysfunction, in patients with angiographic evidence of …