Leukocytes release cytokines and oxygen derived free radicals upon activation. Both superoxide (O<sub>2</sub>) and tumor necrosis factor (TNF) inhibit endothelium-dependent vasodilation in the intact circulation as well as in isolated blood vessels. Superoxide inactivates endothelium-derived relaxing fator (EDRF) rapidly, whereas TNF required 2 h to block EDRF release due to synthesis of adhesive proteins on the surface of neutrophils and/or the expression of their ligands on endothelial cells. Thus, vasodilation to acetylcholine is markedly attenuated by either O<sub>2</sub>or TNF, whereas the vasodilation to NaNO<sub>2</sub> at pH 2.0 or to nitroglycerin is not affected. Superoxide dismutase restores acetylcholine responses to myocardial ischemia followed by reperfusion, whereas cycloheximide restores acetylcholine responses to TNF. This occurs both in the isolated perfused rat heart (perfused without plasma or blood cells) and in isolated perfused cat carotid arteries. EDRF may be important in preserving integrity of vital tissues during ischemic states.