Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers.
BACKGROUND
Cigarette smoking causes endothelial dysfunction, possibly through increased oxidant stress. The enzyme xanthine oxidase produces oxidative free radicals. We tested the hypothesis that xanthine oxidase contributes to endothelial dysfunction in cigarette smokers by administering the inhibitor allopurinol.


RESULTS
Fourteen cigarette smokers (31+/-4 pack years) and 14 age- and sex-matched healthy non-smoking control subjects participated in a single-blinded, randomized, 2-phase crossover study. All subjects had no other risk factors for atherosclerosis. Inhibition of xanthine oxidase was achieved by a single oral dose of 600 mg of allopurinol on the day of the study. Stimulated nitric oxide endothelial responses were assessed by forearm blood flow responses to intraarterial administration of acetylcholine and bradykinin 4 to 7 hours later; basal nitric oxide was assessed using the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA); and nitroprusside was used to assess sensitivity to nitric oxide. Dilatation produced by acetylcholine was significantly less in smokers (254+/-57%) than healthy controls (390+/-55%) (P=0.009). Allopurinol reversed endothelial dysfunction in smokers (acetylcholine, 463+/-78%, P=0.001) without affecting responses in non-smokers (401+/-80%). Bradykinin responses were also impaired in smokers (P=0.003), and improved with allopurinol, though not significantly (P=0.06). Responses to nitroprusside and L-NMMA were not significantly different between smokers and controls and were not altered by allopurinol.


CONCLUSIONS
Smoking-induced endothelial dysfunction of resistance vessels is rapidly reversed with oral allopurinol. These data suggest that xanthine oxidase contributes importantly to endothelial dysfunction caused by cigarette smoking.
Guthikonda
Sashi
S
Department of Internal Medicine and General Clinical Research Center, University of Iowa Carver College of Medicine, Iowa City 52242, USA.
Sinkey
Christine
C
Barenz
Therese
T
Haynes
William G
WG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000493:Allopurinol / Q000494:pharmacology*; D018592:Cross-Over Studies; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D016037:Single-Blind Method; D012907:Smoking; D014664:Vasodilation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D000493:Allopurinol; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase