Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death

Br J Haematol. 2009 May;145(4):506-13. doi: 10.1111/j.1365-2141.2009.07658.x. Epub 2008 Mar 17.


Pulmonary hypertension (PH) in patients with sickle cell disease (SCD) is linked to intravascular haemolysis, impaired nitric oxide bioavailability, renal dysfunction, and early mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases (NOS), is associated with vascular disease in other populations. We determined the plasma concentrations for several key arginine metabolites and their relationships to clinical variables in 177 patients with SCD and 29 control subjects: ADMA, symmetric dimethylarginine (SDMA), NG-monomethyl L-arginine (L-NMMA), N-omega-hydroxy-L-arginine (NOHA), arginine and citrulline. The median ADMA was significantly higher in SCD than controls (0.94 micromol/l vs. 0.31 micromol/l, P < 0.001). Patients with homozygous SCD had a remarkably lower ratio of arginine to ADMA (50 micromol/l vs. 237, P < 0.001). ADMA correlated with markers of haemolysis, low oxygen saturation and soluble adhesion molecules. PH was associated with high levels of ADMA and related metabolites. Higher ADMA level was associated with early mortality, remaining significant in a multivariate analysis. Subjects with homozygous SCD have high systemic levels of ADMA, associated with PH and early death, implicating ADMA as a functional NOS inhibitor in these patients. These defects and others converge on the nitric oxide pathway in homozygous SCD with vasculopathy.

Trial registration: ClinicalTrials.gov NCT00011648.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Anemia, Sickle Cell / blood*
  • Anemia, Sickle Cell / mortality
  • Arginine / analogs & derivatives
  • Arginine / blood*
  • Case-Control Studies
  • Citrulline / blood
  • Follow-Up Studies
  • Hemolysis
  • Humans
  • Hypertension, Pulmonary / blood*
  • Hypertension, Pulmonary / mortality
  • Kidney Diseases / blood
  • Kidney Diseases / mortality
  • Linear Models
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Oxygen / blood
  • Proportional Hazards Models
  • Risk
  • Survival Rate
  • omega-N-Methylarginine / blood


  • omega-N-Methylarginine
  • Citrulline
  • symmetric dimethylarginine
  • N(omega)-hydroxyarginine
  • N,N-dimethylarginine
  • Arginine
  • Nitric Oxide Synthase
  • Oxygen

Associated data

  • ClinicalTrials.gov/NCT00011648