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Additionally, superoxide radicals inactivate EDRF once EDRF is released from endothelial cells, thus preventing EDRF, thought to be nitric oxide (NO), from reaching the vascular smooth muscle cell membrane. This anti-EDRF effect of superoxide radicals can be prevented by superoxide dismutase (SOD). However, superoxide radicals can originate in a variety of cell types, including endothelial cells, since SOD can preserve endothelium-mediated vasodilator responses even in the absence of leukocytes. These mechanisms of induction of endothelial dysfunction may be of considerable significance in ischemia and shock states. Although it has been known for some time that TNF influences leukocyte adhesiveness to endothelial cells, until recently little was known about the effects of TNF on endothelium-dependent vasodilation. First, TNF does not exert any direct vasoactive effect in isolated blood vessels (eg, carotid and coronary arteries) at concentrations up to 10 jig/ml. Second, TNF does not influence the vasoactivity of endothelium-independent dilators (eg, nitroglycerin, NaNO* at pH 2.0) either immediately or after 2 h of incubation with TNF. Third, TNF does not influence endothelium-dependent dilators over incubation periods up to 60 min. Nevertheless, when vessels are incubated with TNF for 90-120 min, there is a profound inhibition of the vasodilation produced by endothelium-dependent dilators (eg, acetylcholine [ACh], adenosine diphosphate [ADP]).