Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris

Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD). Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients. Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine. Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 +/- 67% vs. 145 +/- 106%, p = 0.006) and flow-mediated dilation (4.2 +/- 1.8% vs. 5.4 +/- 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 +/- 7.0%, p < 0.001) but not with placebo. Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766) (J Am Coll Cardiol 2011;58:820-8) (C) 2011 by the American College of Cardiology Foundation