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.