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 Machado, William C. Blackwelder, James G. Taylor VI, Stanley L. Hazen

Research output: Contribution to journalArticle

62 Citations (Scopus)

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 1 2009
Externally publishedYes

Fingerprint

Sickle Cell Anemia
Hemolysis
Pulmonary Hypertension
Nitric Oxide Synthase
Arginine
omega-N-Methylarginine
Nitric Oxide
N,N-dimethylarginine
Citrulline
Mortality
Vascular Diseases
Biological Availability
Multivariate Analysis
Oxygen
Kidney

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Endogenous nitric oxide synthase inhibitors in sickle cell disease : Abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. / Kato, Gregory J.; Wang, Zeneng; Machado, Roberto; Blackwelder, William C.; Taylor VI, James G.; Hazen, Stanley L.

In: British Journal of Haematology, Vol. 145, No. 4, 01.05.2009, p. 506-513.

Research output: Contribution to journalArticle

@article{c4011de67714451e96c00e2c956dc7a9,
title = "Endogenous nitric oxide synthase inhibitors in sickle cell disease: Abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death",
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.",
keywords = "Arginine, Asymmetric dimethylarginine, Pulmonary hypertension, Sickle cell disease, Symmetric dimethylarginine",
author = "Kato, {Gregory J.} and Zeneng Wang and Roberto Machado and Blackwelder, {William C.} and {Taylor VI}, {James G.} and Hazen, {Stanley L.}",
year = "2009",
month = "5",
day = "1",
doi = "10.1111/j.1365-2141.2009.07658.x",
language = "English (US)",
volume = "145",
pages = "506--513",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Endogenous nitric oxide synthase inhibitors in sickle cell disease

T2 - Abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death

AU - Kato, Gregory J.

AU - Wang, Zeneng

AU - Machado, Roberto

AU - Blackwelder, William C.

AU - Taylor VI, James G.

AU - Hazen, Stanley L.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

KW - Arginine

KW - Asymmetric dimethylarginine

KW - Pulmonary hypertension

KW - Sickle cell disease

KW - Symmetric dimethylarginine

UR - http://www.scopus.com/inward/record.url?scp=65349087881&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65349087881&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2141.2009.07658.x

DO - 10.1111/j.1365-2141.2009.07658.x

M3 - Article

VL - 145

SP - 506

EP - 513

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 4

ER -