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Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death
Summary 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 associa...
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| Published in: | British journal of haematology 2009-05, Vol.145 (4), p.506-513 |
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| container_title | British journal of haematology |
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| creator | Kato, Gregory J. Wang, Zeneng Machado, Roberto F. Blackwelder, William C. Taylor 6th, James G. Hazen, Stanley L. |
| description | Summary
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 |
| doi_str_mv | 10.1111/j.1365-2141.2009.07658.x |
| format | article |
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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.</description><identifier>ISSN: 0007-1048</identifier><identifier>EISSN: 1365-2141</identifier><identifier>DOI: 10.1111/j.1365-2141.2009.07658.x</identifier><identifier>PMID: 19344390</identifier><identifier>CODEN: BJHEAL</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Anemia, Sickle Cell - blood ; Anemia, Sickle Cell - mortality ; Anemias. Hemoglobinopathies ; arginine ; Arginine - analogs & derivatives ; Arginine - blood ; asymmetric dimethylarginine ; Biological and medical sciences ; Case-Control Studies ; Citrulline - blood ; Diseases of red blood cells ; Follow-Up Studies ; Hematologic and hematopoietic diseases ; Hemolysis ; Humans ; Hypertension, Pulmonary - blood ; Hypertension, Pulmonary - mortality ; Kidney Diseases - blood ; Kidney Diseases - mortality ; Linear Models ; Medical sciences ; Nitric Oxide Synthase - antagonists & inhibitors ; omega-N-Methylarginine - blood ; Oxygen - blood ; Pneumology ; Proportional Hazards Models ; pulmonary hypertension ; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases ; Risk ; sickle cell disease ; Survival Rate ; symmetric dimethylarginine</subject><ispartof>British journal of haematology, 2009-05, Vol.145 (4), p.506-513</ispartof><rights>Published 2009. This article is a US government work and is in the public domain in the USA</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4478-b9a588b377e36496bbd2b80dca1d6419d78fb759afb6dcdb85dcc80665ab42a93</citedby><cites>FETCH-LOGICAL-c4478-b9a588b377e36496bbd2b80dca1d6419d78fb759afb6dcdb85dcc80665ab42a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21459517$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19344390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kato, Gregory J.</creatorcontrib><creatorcontrib>Wang, Zeneng</creatorcontrib><creatorcontrib>Machado, Roberto F.</creatorcontrib><creatorcontrib>Blackwelder, William C.</creatorcontrib><creatorcontrib>Taylor 6th, James G.</creatorcontrib><creatorcontrib>Hazen, Stanley L.</creatorcontrib><title>Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death</title><title>British journal of haematology</title><addtitle>Br J Haematol</addtitle><description>Summary
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.</description><subject>Anemia, Sickle Cell - blood</subject><subject>Anemia, Sickle Cell - mortality</subject><subject>Anemias. Hemoglobinopathies</subject><subject>arginine</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - blood</subject><subject>asymmetric dimethylarginine</subject><subject>Biological and medical sciences</subject><subject>Case-Control Studies</subject><subject>Citrulline - blood</subject><subject>Diseases of red blood cells</subject><subject>Follow-Up Studies</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hemolysis</subject><subject>Humans</subject><subject>Hypertension, Pulmonary - blood</subject><subject>Hypertension, Pulmonary - mortality</subject><subject>Kidney Diseases - blood</subject><subject>Kidney Diseases - mortality</subject><subject>Linear Models</subject><subject>Medical sciences</subject><subject>Nitric Oxide Synthase - antagonists & inhibitors</subject><subject>omega-N-Methylarginine - blood</subject><subject>Oxygen - blood</subject><subject>Pneumology</subject><subject>Proportional Hazards Models</subject><subject>pulmonary hypertension</subject><subject>Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases</subject><subject>Risk</subject><subject>sickle cell disease</subject><subject>Survival Rate</subject><subject>symmetric dimethylarginine</subject><issn>0007-1048</issn><issn>1365-2141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNqNkc1u1DAUhSMEokPhFZA3sJoM9uTPQWJRqkJBldjA2vLPTePBsQffhE6ejNfDmRmVLd74Sue75_r6ZBlhdMPSebfbsKKu8i0r2WZLabuhTV3xzeFJtnoUnmYrSmmTM1ryi-wF4o5SVtCKPc8uWFuUZdHSVfbnxptwDz5MSLwdo9UkHKwBgrMfe4lArO-tsmOImEqCVv90QDQ4R4xFSMR7IpUPcZCOOPgNDon0hugQIzg52uCRPNixJ_vJDcHLOJN-3kMcwWMS18QAynGKR3RNeglDcDNaXJMQ76UnZsZu8nqRj84G5Ni_zJ510iG8Ot-X2Y9PN9-vb_O7b5-_XF_d5bosG56rVlacq6JpoKjLtlbKbBWnRktm6pK1puGdaqpWdqo22iheGa05retKqnIr2-Iye3vy3cfwawIcxWBx2V56SH8m6mZbFLyuEshPoI4BMUIn9tEOaVvBqFhCEzuxZCOWbMQSmjiGJg6p9fV5xqQGMP8azykl4M0ZkKil66L02uIjlxyrtmJN4j6cuAfrYP7vB4iPX2-XqvgLX064-A</recordid><startdate>200905</startdate><enddate>200905</enddate><creator>Kato, Gregory J.</creator><creator>Wang, Zeneng</creator><creator>Machado, Roberto F.</creator><creator>Blackwelder, William C.</creator><creator>Taylor 6th, James G.</creator><creator>Hazen, Stanley L.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200905</creationdate><title>Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death</title><author>Kato, Gregory J. ; Wang, Zeneng ; Machado, Roberto F. ; Blackwelder, William C. ; Taylor 6th, James G. ; Hazen, Stanley L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4478-b9a588b377e36496bbd2b80dca1d6419d78fb759afb6dcdb85dcc80665ab42a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Anemia, Sickle Cell - blood</topic><topic>Anemia, Sickle Cell - mortality</topic><topic>Anemias. Hemoglobinopathies</topic><topic>arginine</topic><topic>Arginine - analogs & derivatives</topic><topic>Arginine - blood</topic><topic>asymmetric dimethylarginine</topic><topic>Biological and medical sciences</topic><topic>Case-Control Studies</topic><topic>Citrulline - blood</topic><topic>Diseases of red blood cells</topic><topic>Follow-Up Studies</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hemolysis</topic><topic>Humans</topic><topic>Hypertension, Pulmonary - blood</topic><topic>Hypertension, Pulmonary - mortality</topic><topic>Kidney Diseases - blood</topic><topic>Kidney Diseases - mortality</topic><topic>Linear Models</topic><topic>Medical sciences</topic><topic>Nitric Oxide Synthase - antagonists & inhibitors</topic><topic>omega-N-Methylarginine - blood</topic><topic>Oxygen - blood</topic><topic>Pneumology</topic><topic>Proportional Hazards Models</topic><topic>pulmonary hypertension</topic><topic>Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases</topic><topic>Risk</topic><topic>sickle cell disease</topic><topic>Survival Rate</topic><topic>symmetric dimethylarginine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kato, Gregory J.</creatorcontrib><creatorcontrib>Wang, Zeneng</creatorcontrib><creatorcontrib>Machado, Roberto F.</creatorcontrib><creatorcontrib>Blackwelder, William C.</creatorcontrib><creatorcontrib>Taylor 6th, James G.</creatorcontrib><creatorcontrib>Hazen, Stanley L.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>British journal of haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kato, Gregory J.</au><au>Wang, Zeneng</au><au>Machado, Roberto F.</au><au>Blackwelder, William C.</au><au>Taylor 6th, James G.</au><au>Hazen, Stanley L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death</atitle><jtitle>British journal of haematology</jtitle><addtitle>Br J Haematol</addtitle><date>2009-05</date><risdate>2009</risdate><volume>145</volume><issue>4</issue><spage>506</spage><epage>513</epage><pages>506-513</pages><issn>0007-1048</issn><eissn>1365-2141</eissn><coden>BJHEAL</coden><abstract>Summary
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.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>19344390</pmid><doi>10.1111/j.1365-2141.2009.07658.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anemia, Sickle Cell - blood Anemia, Sickle Cell - mortality Anemias. Hemoglobinopathies arginine Arginine - analogs & derivatives Arginine - blood asymmetric dimethylarginine Biological and medical sciences Case-Control Studies Citrulline - blood Diseases of red blood cells Follow-Up Studies Hematologic and hematopoietic diseases Hemolysis Humans Hypertension, Pulmonary - blood Hypertension, Pulmonary - mortality Kidney Diseases - blood Kidney Diseases - mortality Linear Models Medical sciences Nitric Oxide Synthase - antagonists & inhibitors omega-N-Methylarginine - blood Oxygen - blood Pneumology Proportional Hazards Models pulmonary hypertension Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases Risk sickle cell disease Survival Rate symmetric dimethylarginine |
| title | Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death |
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