Effects of Xanthine Oxidase Inhibition With Allopurinol on Endothelial Function and Peripheral Blood Flow in Hyperuricemic Patients With Chronic Heart Failure: Results From 2 Placebo-Controlled Studies

Abstract

Background — In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)–derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results — In 10 CHF patients with normal serum uric acid (UA) levels (315±42 μmol/L) and 9 patients with elevated UA (535±54 μmol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 μg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients ( P <0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558±21 μmol/L, range 455 to 743 μmol/L), treatment reduced UA by >120 μmol/L in all patients (mean reduction 217±15 μmol/L, P <0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P =0.027) and legs (+23%, P =0.029). Flow-dependent flow improved by 58% in arms ( P =0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment ( P <0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment ( r =0.63, P <0.05). Conclusions — In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.