Published Online
on November 27, 2006

A more recent version of this article appeared on December 5, 2006

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Submitted on July 24, 2006
Revised on September 26, 2006
Accepted on September 28, 2006

High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid

Jacob George MBChB, MRCP, Elaine Carr RGN, BN, Justine Davies MD, MRCP, J. J.F. Belch MD, FRCP, and Allan Struthers MD, FRCP, FESC^*

From the Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK.

^* To whom correspondence should be addressed. E-mail: a.d.struthers{at}dundee.ac.uk.

Background--Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol.

Methods and Results--Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II-III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean±SEM]: 240.31±38.19% versus 152.10±18.21% versus 73.96±10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitroprusside response was unchanged by all treatments. Vitamin C and acetylcholine coinfusion data showed that 600 mg/d allopurinol completely abolished the oxidative stress that was sensitive to high-dose vitamin C.

Conclusions--For the first time, we have shown that a steep dose-response relationship exists between allopurinol and its effect on endothelial function. We also showed that the mechanism of improvement in endothelial function with allopurinol lies in its ability to reduce vascular oxidative stress and not in urate reduction. The reduction in vascular oxidative stress was profound because high-dose allopurinol totally abolished the oxidative stress that was sensitive to the high-dose vitamin C that was used in this study.

Key words: endothelium • free radicals • heart failure • allopurinol • uric acid

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