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Recent data suggest that hydroxyurea (HU) increases the production of nitric oxide (NO), a potent vasodilator. NO is normally metabolized from l-Arginine (Arg). However, in vitro and animal experiments suggest that HU is the NO donor itself. In contrast, a recent study indicates that nitric oxide synthase (NOS) may play a role. Since adults with sickle cell disease (SCD) are Arg-deficient, Arg availability may limit the ability of HU to maximally impact NO production if an NOS mechanism is involved. The authors have previously shown that Arg supplementation alone induces a paradoxical decrease in NO metabolite (NOx) production.The authors studied the effects of HU and Arg supplementation on NOx production. HU alone or HU + Arg was administered to patients with SCD at steady state, and sequential levels of Arg, serum NOx and exhaled NO were followed over 4 hours.After HU + Arg, all patients demonstrated a significant increase in serum NOx production within 2 hours. When the same patients were treated with HU alone (5.1 ± 2 μmol/L), a mixed response occurred. NOx levels increased in four patients and decreased in one patient (-23.3 μmol/L).While Arg alone does not increase serum NOx production in SCD patients at steady state, it does when given together with HU. Hence, co-administration of Arg with HU may augment the NOx response in SCD and improve utilization of Arg in patients at steady state.