Effect of dexrazoxane on homocysteine-induced endothelial dysfunction in normal subjects.
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.


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 micromol/L at baseline to 14.2+/-1.3 micromol/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 micromol/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.
Department of Medicine, Peking Union Medical College Hospital, Beijing, China.
Haoyi
H
Zheng
Clarito
C
Dimayuga
Alhakam
A
Hudaihed
Stuart D
SD
Katz
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D018592:Cross-Over Studies; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D011929:Razoxane / Q000494:pharmacology*
D000975:Antioxidants; D002317:Cardiovascular Agents; D002614:Chelating Agents; D006710:Homocysteine; D011929:Razoxane; D008715:Methionine; D007501:Iron