Angiotensin-converting enzyme (ACE) inhibition has been shown to improve endothelium-dependent vasodilator responsiveness, but the contribution and mechanism of enhanced nitric oxide (NO) bioactivity to this effect in patients with coronary artery disease are unknown. We investigated the effect of ACE inhibition on brachial artery dilator responsiveness to increased shear stress after forearm ischemia by ultrasonography as a bioassay for endothelial NO available to vascular smooth muscle in 9 men with coronary artery disease. Serum nitrogen oxides were measured after 3 days of nitrate-restricted diet as an index of endothelial NO release. Patients received quinapril 20 to 40 mg/day for 8 weeks. Relative to pretreatment measurements, quinapril increased flow-mediated dilation (from 2.4+/-0.4 to 10.8+/-2.2, p <0.001), with significant improvement persisting 1 week after discontinuation of therapy (6.7+/-2.5%, p <0.01). However, quinapril decreased serum nitrogen oxide levels by 19+/-17% compared with pretreatment values (from 58.2+/-19.0 to 46.0+/-13.3 micromol/L, p <0.01). Thus, ACE inhibitor therapy with quinapril selectively improves endothelium-dependent vasodilator responsiveness by increased NO bioactivity in relation to vascular smooth muscle in patients with coronary artery disease, an effect achieved at a lower rate of NO release from the endothelium. These findings suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall and protect NO from oxidative inactivation. This effect may reduce endothelial NO synthesis required for vasomotor regulation.