The role of urate and xanthine oxidase inhibitors in cardiovascular disease.
Many studies have shown a strong correlation between urate levels and cardiovascular disease. The formation of urate is complex as the same enzyme that produces urate, xanthine oxidase (XO) also catalyzes the formation of reactive oxygen species (ROS). There is some evidence that the urate molecule has free radical scavenging properties in vitro and acute infusions of urate improve endothelial function in at-risk populations. High levels of ROS are clearly linked to worse outcome in a variety of conditions. Allopurinol has been the archetypal XO inhibitor for over 40 years. Small studies have demonstrated its beneficial effects, mainly in heart failure but also in a variety of other cohorts of patients with cardiovascular risk. It is a safe agent, provided suitable patients are chosen and monitored carefully. Newer promising agents like oxypurinol have not shown the expected benefits in larger multicentered studies. This review looks at the biology of urate, its role in cardiovascular disease, the possible mechanisms by which XO inhibitors exert their beneficial effect on endothelial dysfunction, and examines the possible causes for the failure of newer agents to live up to expectations.
George
Jacob
J
Department of Clinical Pharmacology, University of Dundee, Dundee, UK.
Struthers
Allan D
AD
D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D014527:Uric Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase