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

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 Endotheliumderived 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. NO in Health and Atherosclerosis: Relationship With Risk Factors and Hemodynamic Stress 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 atherosclerosis. The concept of endothelial vasodilator dysfunction in atherosclerotic human coronary arteries was reinforced by similar findings when other stimuli to NO release were tested, including flow-mediated dilation, sympathetic activation, serotonin, and adenosine diphosphate.4 The loss of endothelium-dependent dilation occurs in the earliest stages of atherosclerosis. In fact, it has been linked to each of the known atherogenic risk factors, including several forms of dyslipidemia, hypertension, diabetes mellitus, cigarette smoking, aging, menopause, family history of premature atherosclerosis, and hyperhomocysteinemia.8–10 The endothelium is a direct, sensitive target for the damaging effects of atherogenic risk factors, as evidenced from the experimental introduction of risk factors into healthy subjects. For example, elevation of blood homocysteine by administration of its precursor methionine,11 generation of lipoprotein remnant