title: Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris.
abstract: OBJECTIVE
  The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).
  
  
  BACKGROUND
  Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.
  
  
  RESULTS
  Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo.
  
  
  CONCLUSIONS
  Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766).
authors.affiliation: Division of Medical Sciences, University of Dundee, Ninewells Hospital Medical School, Dundee, UK. drrajendra_ns@rediffmail.com
authors.forename: Narasimharajapura S
authors.initials: NS
authors.lastname: Rajendra
authors.forename: Sheila
authors.initials: S
authors.lastname: Ireland
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Jill J F
authors.initials: JJ
authors.lastname: Belch
authors.forename: Chim C
authors.initials: CC
authors.lastname: Lang
authors.forename: Allan D
authors.initials: AD
authors.lastname: Struthers
mesh_terms: D000368:Aged; D000493:Allopurinol / Q000008:administration & dosage*; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D000975:Antioxidants / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D001783:Blood Flow Velocity / Q000502:physiology; D001916:Brachial Artery / Q000000981:diagnostic imaging; D003324:Coronary Artery Disease / Q000453:epidemiology / 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 / Q000008:administration & dosage*; D028441:F2-Isoprostanes / Q000097:blood; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D010991:Plethysmography; D012039:Regional Blood Flow / Q000502:physiology; D014463:Ultrasonography
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D020097:Natriuretic Peptide, Brain; D000493:Allopurinol; D001205:Ascorbic Acid