the endothelium - derived relaxing factor , recently identified as nitric oxide ( no ) or a closely related compound , has potent antiatherosclerotic properties . no released from endothelial cells works in concert with prostacyclin to inhibit platelet aggregation ; it inhibits the attachment of neutrophils to endothelial cells and the expression of adhesion molecules . therefore , under all conditions where an absolute or relative no deficit is encountered , the process of atherosclerosis is being initiated or accelerated . the half - life of no , and therefore its biological activity , is decisively determined by oxygen - derived free radicals such as superoxide ( o2 ) . super - oxide reacts rapidly with nitric oxide ( no ) to form the highly reactive intermediate peroxynitrite ( onoo ) . the rapid bimolecular reaction between no and o2 , yielding onoo ( rate constant 1.9  10/m / s ) , is about 5 to 10 times faster than the dismutation of o2 by superoxide dismutase . therefore , onoo formation represents a major potential pathway of no reactivity depending on the rates of tissue o2 production . peroxynitrite is also a highly reactive intermediate that may cause oxidative damage to lipids , proteins , and dna . there is a growing body of evidence that endothelial dysfunction in the setting of hypercholesterolemia , diabetes mellitus , hypertension , or chronic smoking is often a consequence of enhanced no degradation by oxygen - derived free radicals rather than diminished no formation due to decreased activity and/or expression of the nitric oxide synthase . therefore , in many instances the most effective approach to improve no bioavailability in the presence of risk factors is to lower o2 levels , eg by treatment withscavenging agents or by the administration of drugs that specifically inhibit o2 production . the effects of antioxidants such as vitamin c , - and -carotene , or vitamin e on the prognosis in patients with coronary - artery disease are very disappointing . so far , there is just one study showing a reduction in coronary - event rates in patients with angiographically evident coronary - artery disease ( the cambridge heart antioxidant study [ chaos ] trial ) after treatment with vitamin e ( 400 - 800 iu / day ) , although the overall prognosis in these patients was not improved . other randomized trials , such as the alpha - tocopherol , beta carotene cancer prevention study , the gruppo italiano per lo studio della sopravvivenza nell'infarto miocardico ( gissi - prevenzione trial ) , and the heart outcomes prevention evaluation ( hope )   study , failed to demonstrate any improvement of the prognosis in patients with coronary artery disease . how can one explain the lack of benefit from antioxidants despite the known causal role of oxidative stress in the initiation and progression of atherosclerosis ? . however , the rate constant for the reaction of vitamins e and c with o2 is much slower(1000- to 10 000-fold ) than the rate constant for the reaction between no and o2 . therefore , in order to scavenge o2 , antioxidants must be administered in very high con centrations , to reach compartments where o2 is formed ( such as endothelial and smooth - muscle cells ) . when high concentrations of vitamins are used , however , pro - oxidative effects may come into play . for example , low concentrations of vitamin e improved endothelial function in cholesterol - fed animals , while high concentrations of the vitamin had the opposite effects and even worsened endothelial function . one explanation for this is that when vitamin e reacts with a radical , it becomes the vitamin - e radical , ie the tocopheroxyl radical , which itself may participate in pro - oxidative events . these findings may indicate that the optimal dose of antioxidants must be titrated in order to improve rather than worsen vascular function . the phenomenon may at least partly explain the failure of antioxidants to improve prognosis in patients with coronary - artery disease . it is also possible that combinations of antioxidants , such as vitamins c and e , need to be used to prevent accumulation of the vitamin - e radical . the effect of angiotensin - converting - enzyme ( ace ) inhibitors on the progression of atherosclerosis and endothelial function has been studied in several animal models and in patients with coronary - artery disease . it has been consistently shown that ace inhibition slows the progression of atherosclerosis   and improves impaired endothelial dysfunction   without altering plasma cholesterol levels . in contrast to the published findings in studies of antioxidants , ace inhibitors seem to have a beneficial influence on the prognosis in patients with coronary - artery disease . how do ace inhibitors beneficially influence vascular function in atherosclerosis ? angiotensin ii , in turn , stimulates the release of endothelin-1 from endothelial cells and induces the expression of the preproendothelin gene in endothelial and smooth - muscle cells . inhibition of kininase ii , which is responsible for the breakdown of bradykinin , leads to high local concentrations of bradykinin . this substance , in turn , is a potent stimulus for the release of endothelium - derived hyperpolarizing factor , no , and prostacyclin . a novel , recently identified , mechanism contributes to the detrimental effects of angiotensin ii on vascular superoxide production . angiotensin ii has been shown to increase vascular superoxide production by activating an nadh - driven oxidase , one of the most significant superoxide - producing enzymes in endothelial and smooth - muscle cells . recent studies with hypercholesterolemic animals   and patients with coronary - artery disease   indicate that activation of this enzyme contributes considerably to endothelial dysfunction and early plaque formation . the stimulatory effects of angiotensin ii on the activity of the hadh - driven oxidase would suggest that in the presence of an activated renin - angiotensin system ( local or circulating ) , vascular dysfunction due to increased vascular superoxide production is likely . indeed , there is a large body of literature providing evidence that the renin - angiotensin system is causally linked to the development and progression of atherosclerosis . incubation in vitro of cultured smooth - muscle cells with native low - density lipoproteins ( ldls ) increases the expression of the angiotensin ii receptor subtype at1 . similar phenomena have been observed in animals fed cholesterol , in animals that are hyperlipidemic because of an ldl - receptor defect , and in patients with hypercholesterolemia . angiotensin ii facilitates the recruitment of monocytes / macrophages into the vessel wall by stimulating the production of the monocyte chemoattractant protein ( mcp-1 ) and vascular - adhesion molecules . further indirect support for the involvement of the renin - angiotensin system in the development of atherosclerosis was provided by studies testing the antiathero - sclerotic properties of ace inhibitors and of at1-receptor antagonists . these studies have shown that both treatment regimens beneficially influence endothelial function , reduce oxidative stress within vascular tissue by inhibiting the vascular nadh oxidase , and , therefore , retard the formation of atherosclerotic plaques . the recently published results of the hope study seem to strengthen the idea that inhibition of the renin - angiotensin system , rather than treatment with the classical antioxidant -tocopherol , beneficially affects the prognosis in patients with coronary - artery disease . treatment with ramipril significantly lowered the risk of cardiovascular mortality and nonfatal cardiovascular events in high - risk patients who had vascular disease or diabetes plus one known cardiovascular risk factor . thus , it may be concluded that inhibition of the renin - angiotensin system and the subsequent inhibition of superoxide - producing enzymes provide a better antioxidative regimen than the administration of classic antioxidants , which merely scavenge already formed reactive oxygen species .