Nitric Oxide Activity in the Atherosclerotic Human Coronary Circulation

Objectives. We determined the activity of nitric oxide at rest and after acetylcholine in the atherosclerotic human coronary circulation. Background. Although responses to acetylcholine, an endothelium-dependent vasodilator, are abnormal in patients with coronary atherosclerosis, whether this reflects abnormal nitric oxide activity in humans in vivo has not been investigated previously. Methods. We investigated the effects of intracoronary image-NG-monomethyl arginine (image-NMMA), specific antagonist of nitric oxide synthesis, on coronary vascular resistance and epicardial coronary artery diameter at rest and after acetylcholine in 24 patients with coronary artery disease and in 12 subjects with angiographically normal coronary arteries who were free from atherosclerotic risk factors. Results. With image-NMMA, the 13 ± 4% (mean ± SEM) increase in coronary vascular resistance and the 4 ± 1% lumen diameter narrowing in atherosclerotic patients were lower than the 38 ± 9% increase in resistance and the 15 ± 2% decrease in diameter (both p < 0.01) observed in normal control subjects, indicating reduced basal nitric oxide activity in atherosclerosis. The degree of angiographic atherosclerotic narrowing did not correlate with the magnitude of diameter reduction. Acetylcholine-induced coronary epicardial and microvascular dilation was also depressed in atherosclerotic patients (32.2 ± 9% reduction in coronary vascular resistance with 10−6 mol/liter acetylcholine) compared with normal control subjects (65.5 ± 2% decrease, p < 0.01). image-NMM inhibited acetylcholine-induced epicardial and microvascular vasodilation in both patient groups, but the inhibition was greater in normal control subjects than in atherosclerotic patients, indicating that stimulation of nitric oxide activity by acetylcholine is reduced in atherosclerotic patients compared with normal control subjects. Coronary vascular dilation with sodium nitroprusside was similar in both groups and was not suppressed by image-NMMA. Furthermore, image-arginine reversed the constrictor effects of image-NMMA, indicating that the action of image-NMM is specifically caused by inhibition of nitric oxide production from image-arginine. Conclusions. These findings indicate that 1) there is reduced basal activity of nitric oxide in the human atherosclerotic epicardial and microvascular coronary circulation; and 2) acetylcholine-induced coronary vascular dilation is at least partly due to stimulation of the activity of nitric oxide, and the reduced response to acetylcholine is due to attenuation in the stimulated activity of nitric oxide in patients with atherosclerosis.