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

Gregory J. Kato, Zeneng Wang, Roberto F. MacHado, William C. Blackwelder, James G. Taylor VI, Stanley L. Hazen

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

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 μmol/l vs. 0·31 μmol/l, P < 0·001). Patients with homozygous SCD had a remarkably lower ratio of arginine to ADMA (50 μmol/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.

Original languageEnglish (US)
Pages (from-to)506-513
Number of pages8
JournalBritish journal of haematology
Volume145
Issue number4
DOIs
StatePublished - May 2009

Keywords

  • Arginine
  • Asymmetric dimethylarginine
  • Pulmonary hypertension
  • Sickle cell disease
  • Symmetric dimethylarginine

ASJC Scopus subject areas

  • Hematology

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