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 .
 the results of recent randomized trials to test the influence of antioxidants on coronary - event rates and prognosis in patients with coronary - artery disease were disappointing . in none of these studies did the use of vitamin e improve prognosis . 
 in contrast , treatment of coronary - artery disease with angiotensin - converting - enzyme ( ace ) inhibitors reduced coronary - event rates and improved prognosis . 
 ace inhibition prevents the formation of angiotensin ii , which has been shown to be a potent stimulus of superoxide - producing enzymes in atherosclerosis . 
 the findings suggest that inhibition of superoxide production at enzymatic levels , rather than symptomatic superoxide scavenging , may be the better choice of treatment . 
The oxidative-stress concept of atherosclerosis: the rationale for the use of antioxidants
Effects of antioxidants in clinical studies
Are angiotensin-converting-enzyme inhibitors the better `antioxidants'?