High-dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid.
From: Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Circulation
- Publish Date: Dec 2006
- ISSN: 1524-4539
- Volume: 114
- Issue: 23
- Pages: 2508-16
- Medium: Internet
- Language: English
- Citation (JAMA): George Jacob, Carr Elaine, Davies Justine, et al. High-dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid.. Circulation Dec 2006;114:2508-16
Abstract
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.
Mesh Headings (Keywords): Acetylcholine, Aged, Allopurinol, Ascorbic Acid, Blood Pressure, Cardiac Output, Low, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Endothelium, Vascular, Enzyme Inhibitors, Female, Humans, Male, Middle Aged, Nitroprusside, Oxidative Stress, Probenecid, Regional Blood Flow, Uric Acid, Uricosuric Agents, Vasodilator Agents
Check for Full Text / PubMed Unique Identifier (PMID): 17130343
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.