Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease.
OBJECTIVE
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 (NO(x)) production.


METHODS
The authors studied the effects of HU and Arg supplementation on NO(x) production. HU alone or HU + Arg was administered to patients with SCD at steady state, and sequential levels of Arg, serum NO(x) and exhaled NO were followed over 4 hours.


RESULTS
After HU + Arg, all patients demonstrated a significant increase in serum NO(x) production within 2 hours. When the same patients were treated with HU alone (5.1 +/- 2 micromol/L), a mixed response occurred. NO(x) levels increased in four patients and decreased in one patient (-23.3 micromol/L).


CONCLUSIONS
While Arg alone does not increase serum NO(x) production in SCD patients at steady state, it does when given together with HU. Hence, co-administration of Arg with HU may augment the NO(x) response in SCD and improve utilization of Arg in patients at steady state.
Morris
Claudia R
CR
Department of Emergency Medicine, Children's Hospital and Research Center at Oakland, Oakland, California 94609, USA. cmorris@mail.cho.org
Vichinsky
Elliott P
EP
van Warmerdam
Jane
J
Machado
Lorenzo
L
Kepka-Lenhart
Diane
D
Morris
Sidney M
SM
Kuypers
Frans A
FA
D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002648:Child; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D016166:Free Radical Scavengers / Q000032:analysis*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000032:analysis*
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D001120:Arginine; D006918:Hydroxyurea