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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:e15.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effect of Dexrazoxane on Homocysteine-Induced Endothelial Dysfunction in Normal Subjects

Haoyi Zheng; Clarito Dimayuga; Alhakam Hudaihed; Stuart D. Katz

From Department of Medicine (H.Z.), Peking Union Medical College Hospital, Beijing, China; the Department of Medicine (C.D.), Columbia University College of Physicians and Surgeons, New York City, NY; and the Department of Medicine (A.H., S.D.K.), Yale University School of Medicine, New Haven, Conn.

Correspondence to Stuart D. Katz, MD, Yale University School of Medicine, 135 College St, Suite 301, New Haven, CT 06510. E-mail stuart.katz@yale.edu

Objective— Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects.

Methods and Results— Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of L-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m²) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1±0.4 µmol/L at baseline to 14.2±1.3 µmol/L at 4 hours, P<0.001) and decreased FMD (from 3.8±0.7% at baseline to 1.2±0.5% at 4 hours, P=0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9±1.1 µmol/L at 4 hours, P=0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5±0.5% at baseline to 5.9±1.1% at 4 hours, P<0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane.

Conclusions— Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects.

Key Words: methionine • vascular endothelium • oxidative stress • chelation • iron

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