title: High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
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.
  
  
  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.
authors.affiliation: Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Elaine
authors.initials: E
authors.lastname: Carr
authors.forename: Justine
authors.initials: J
authors.lastname: Davies
authors.forename: J J F
authors.initials: JJ
authors.lastname: Belch
authors.forename: Allan
authors.initials: A
authors.lastname: Struthers
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002303:Cardiac Output, Low / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011339:Probenecid / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014527:Uric Acid / Q000378:metabolism*; D014528:Uricosuric Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014528:Uricosuric Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D014527:Uric Acid; D000493:Allopurinol; D000109:Acetylcholine; D011339:Probenecid; D001205:Ascorbic Acid