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Vol. 55, Issue 6, 1006-1010, June 1999
Laboratory of Pharmacology and Chemistry, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (R.E.G., R.P.M); Department of Medicine,
University of North Carolina, Chapel Hill, North Carolina (E.D.I.,
E.P.O.); and Department of Microbiology, Kumamoto University of
Medicine, Kumamoto, Japan (H.M.)
The clinical efficacy of hydroxyurea (HU) in the treatment of sickle
cell anemia has mainly been attributed to increased levels of fetal
hemoglobin (HbF), which reduces the tendency for sickle hemoglobin to
polymerize, thereby reducing the frequency of the vaso-occlusive
phenomena associated with the disease. However, benefits from HU
treatment in patients have been reported in advance of increased HbF
levels. Thus, it has been suggested that other hydroxyurea-dependent
mechanisms may, in part, account for its clinical efficacy. We have
previously demonstrated that HU is metabolized in rats to release
nitric oxide and, therefore, postulated the same to occur in humans.
However, to our knowledge, evidence of nitric oxide production from HU
metabolism in humans has yet to be demonstrated. Here we report that
oral administration of HU for the treatment of sickle cell anemia
produced detectable nitrosyl hemoglobin. The nitrosyl hemoglobin
complex could be detected as early as 30 min after administration and
persisted up to 4 h. Our observations support the hypothesis that
the ability of HU to ease the vaso-occlusive phenomena may, in part, be
attributed to vasodilation and/or decreased platelet activation induced
by HU-derived nitric oxide well in advance of increased HbF levels.
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