Animal models of atherosclerosis have shown that oxidized lipoproteins and free radical molecules oxidize nitric oxide (NO) into biologically inert or toxic molecules, with the net effect of reduced NO bioactivity. In order to determine the mechanism of angiotensin converting enzyme (ACE) inhibitor-mediated improvement in endothelium-dependent vasodilation in coronary artery disease (CAD), we administered quinapril 20-40 mg daily for 8 weeks to 9 men with CAD, with measures of brachial artery flow-mediated dilation (FMD) following forearm ischemia and serum NO2/NO3 on a 3-day nitrogen-free diet. We also measured endothelium-independent dilation after nitroglycerin (TNG). Data = mean +/- SD. Rx=therapy. FMD increased from 2.4+/-0.4% at baseline to 10.8+/-2.2% (p,/001), and was 6.7+/-2.5% one week following discontinuation of therapy. Serum nitrogen oxide levels were 58.2+/-19.0 micromol/L at baseline, but declined to 46.0+/-13.3 micromol/L after 8 weeks of therapy (p<.02), and increased to 56.1+/-14.8 micromol/L one week off therapy. There was no effect of quinapril on TNG-induced dilation (12.5+/-2.8% at baseline, 14.1+/-3.4% after 8 weeks of therapy, and 13.7+/-2.9% one week off therapy. Thus, significant improvement in FMD following 8 weeks of quinapril therapy was accompanied by reduction in the luminal release of NO into the bloodstream. These data suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall, with protection of NO from oxidation. Reduced NO degradation in turn may reduce the rate of NO synthesis required for vasomotor regulation. We conclude that ACE inhibitor therapy improves NO bioactivity with enhanced endothelium-dependent vasodilator responsiveness that is accomplished at a lower rate of NO synthesis.