Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies.
BACKGROUND
In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies.


RESULTS
In 10 CHF patients with normal serum uric acid (UA) levels (315+/-42 micromol/L) and 9 patients with elevated UA (535+/-54 micromol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 microg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P<0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558+/-21 micromol/L, range 455 to 743 micromol/L), treatment reduced UA by >120 micromol/L in all patients (mean reduction 217+/-15 micromol/L, P<0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05).


CONCLUSIONS
In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.
Doehner
Wolfram
W
Clinical Cardiology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Schoene
Nina
N
Rauchhaus
Mathias
M
Leyva-Leon
Francisco
F
Pavitt
Darrell V
DV
Reaveley
David A
DA
Schuler
Gerhard
G
Coats
Andrew J S
AJ
Anker
Stefan D
SD
Hambrecht
Rainer
R
D000284:Administration, Oral; D000368:Aged; D000481:Allantoin / Q000097:blood; D000493:Allopurinol / Q000008:administration & dosage*; D001783:Blood Flow Velocity / Q000187:drug effects; D002908:Chronic Disease; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005542:Forearm / Q000098:blood supply; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D014527:Uric Acid / Q000097:blood*; D014664:Vasodilation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014527:Uric Acid; D000481:Allantoin; D000493:Allopurinol; D014969:Xanthine Oxidase