The endothelium-derived relaxing factor, recently identified as nitric oxide (NO [1]) or a closely related compound [2], 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. NO in high concentrations inhibits the proliferation of smooth-muscle cells. 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^-) [3]. 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 × 10¹⁰/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.

The effects of antioxidants such as vitamin C, α- and β-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 [4]. Other randomized trials, such as the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study [5], the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI-Prevenzione trial) [6], and the Heart Outcomes Prevention Evaluation (HOPE) [7] study, failed to demonstrate any improvement of the prognosis in patients with coronary artery disease.

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 [9] and improves impaired endothelial dysfunction [10] 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 [11]. How do ACE inhibitors beneficially influence vascular function in atherosclerosis? ACE inhibition prevents formation of angiotensin II, one of the most potent vasoconstrictors. 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. Another important aspect is that endothelial kininase II is identical with ACE. 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 [12], one of the most significant superoxide-producing enzymes in endothelial and smooth-muscle cells. Recent studies with hypercholesterolemic animals [13] and patients with coronary-artery disease [14] indicate that activation of this enzyme contributes considerably to endothelial dysfunction and early plaque formation.