930-105 Xanthine-Oxidase Inhibition Improves Coronary Endothelium-Mediated Relaxation in Patients with Early Atherosclerosis

Atherosclerosis impairs endothelium-mediated relaxation (EMR) in the human coronary artery. Endothelial xanthine oxidase (XO) generates superoxide anion, an inactivator of nitric oxide. In the hypercholesterolemic rabbit aorta, endothelial XO-induced superoxide anion production is reduced by oxypurinol, restoring normal EMR. We hypothesized that XO inhibition with allopurinol would improve coronary EMR in patients with atherosclerosis. To assess the effects of XO inhibition on EMR, we studied 18 patients (risk factors + mild atherosclerosis) with serial intracoronary infusions of acetylcholine (ACH) (10 -8 to 10 -6 M) before and after IV allopurinol (150 mg/m 2 over one hour) (n = 8) or placebo (n = 10). All patients received intracoronary infusions of an endothelium-independent dilator ladenosine [2.2 mg/min] or nitroglycerin [40 μg]). A blinded analysis of arterial responses was performed using automated quantitative angiography. In Placebo patients, serial responses to ACH were identical (-19 ± 4%/ - 18 ± 5%, P = ns) (expressed as percent change pre/post placebo). However, in Allopurinol patients, ACH responses were dramatically improved after IV allopurinol (-20 ± 5%/-10 ± 5%, P = 0.01). Allopurinol did not affect resting coronary dimensions. Endotheliumin dependent responses were similar in both groups. Thus, XO inhibition improves coronary artery EMR in patients with coronary risk factors and early atherosclerosis. This suggests that XO-generated superoxide anion, via destruction of nitric oxide, contributes to the impairment of EMR in coronary atherosclerosis.