Published Online
on January 6, 2003

A more recent version of this article appeared on January 28, 2003

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Submitted on August 12, 2002
Revised on October 8, 2002
Accepted on October 8, 2002

Xanthine Oxidase Inhibition Reverses Endothelial Dysfunction in Heavy Smokers

Sashi Guthikonda MD, MPH, Christine Sinkey RN, Therese Barenz RN, and William G. Haynes MD, FRCP^*

From the Department of Internal Medicine and General Clinical Research Center, University of Iowa Carver College of Medicine, Iowa City.

^* To whom correspondence should be addressed. E-mail: william-g-haynes{at}uiowa.edu.

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.

Methods and 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.

Key words: atherosclerosis • nitric oxide • endothelium • smoking

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