Endothelial dysfunction is on of the signs of early atherosclerosis, and also a major component of ischemia-reperfusion injury. Several factors affect endothelial function, but the presence of reactive oxygen species in the vessel wall and the ability of endothelium to generated nitric oxide (NO) seem to be the most important determinants of endothelial function. Due to abnormalities in NOS, the generation of free oxygen radicals increases, and the level of NO decreases during an ischemic episode. This leads to significant alterations in the endothelial function. Under ischemic conditions, nitric oxide synthase produces superoxide (.O2-) in excess of nitric oxide (NO). Superoxide can react with the surrounding nitric oxide to produce a potent oxidizing agent, peroxynitrite (ONOO-). These oxygen radicals are thought to contribute to the development of ischemia-reperfusion injury in humans. NO has been shown to play a significant role in reducing reperfusion injury in humans. The group from our institution demonstrated this where reperfusion injury in the forearm of human subjects was attenuated by the administration of tetrahydrobiopterin (BH4), a cofactor for NOS that leads to the production of NO (unpublished data, Baballiaros et al.). The time course for oxidative marker expression, such as NO, after ischemia-reperfusion injury is expected to occur as early as 2.5 to 5 minutes after reperfusion. Several studies have examined the time course of NO, nitrosyl hemoglobin, glutathione reduction-oxidation, and hydro peroxides. In a study conducted by Mochizuki et al, describing an arterial flow mediated dilation model, NO attained a peak value with a first-order time delay and the peak level NO concentration was linearly correlated with perfusion rate in each vessel. It must be noted, however, that the peak and duration of the levels are somewhat variable and depend on perfusion flow and the diameter of the vessel.