Dimethylarginines

Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria

Joe Brice Weinberg, Tsin W. Yeo, Jackson P. Mukemba, Salvatore M. Florence, Alicia D. Volkheimer, Hao Wang, Youwei Chen, Matthew Rubach, Donald L. Granger, Esther D. Mwaikambo, Nicholas M. Anstey

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.

Methods: We studied Tanzanian children ages 4–8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.

Results: 
ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde­pendent­ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.

Conclusions: 
In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children. 

Original languageEnglish
Pages (from-to)913-922
Number of pages10
JournalJournal of Infectious Diseases
Volume210
Issue number6
DOIs
Publication statusPublished - 15 Sep 2014

Fingerprint

Falciparum Malaria
Arginine
Nitric Oxide
Malaria
Angiopoietin-2
Biological Availability
Arginase
Hemoglobins
Cerebral Malaria
dimethylarginine
N,N-dimethylarginine
Nitric Oxide Synthase
Lactic Acid
Therapeutics

Cite this

Weinberg, Joe Brice ; Yeo, Tsin W. ; Mukemba, Jackson P. ; Florence, Salvatore M. ; Volkheimer, Alicia D. ; Wang, Hao ; Chen, Youwei ; Rubach, Matthew ; Granger, Donald L. ; Mwaikambo, Esther D. ; Anstey, Nicholas M. / Dimethylarginines : Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria. In: Journal of Infectious Diseases. 2014 ; Vol. 210, No. 6. pp. 913-922.
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title = "Dimethylarginines: Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria",
abstract = "Background: Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.Methods: We studied Tanzanian children ages 4–8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.Results: ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde­pendent­ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.Conclusions: In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children. ",
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author = "Weinberg, {Joe Brice} and Yeo, {Tsin W.} and Mukemba, {Jackson P.} and Florence, {Salvatore M.} and Volkheimer, {Alicia D.} and Hao Wang and Youwei Chen and Matthew Rubach and Granger, {Donald L.} and Mwaikambo, {Esther D.} and Anstey, {Nicholas M.}",
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Weinberg, JB, Yeo, TW, Mukemba, JP, Florence, SM, Volkheimer, AD, Wang, H, Chen, Y, Rubach, M, Granger, DL, Mwaikambo, ED & Anstey, NM 2014, 'Dimethylarginines: Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria', Journal of Infectious Diseases, vol. 210, no. 6, pp. 913-922. https://doi.org/10.1093/infdis/jiu156

Dimethylarginines : Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria. / Weinberg, Joe Brice; Yeo, Tsin W.; Mukemba, Jackson P.; Florence, Salvatore M.; Volkheimer, Alicia D.; Wang, Hao; Chen, Youwei; Rubach, Matthew; Granger, Donald L.; Mwaikambo, Esther D.; Anstey, Nicholas M.

In: Journal of Infectious Diseases, Vol. 210, No. 6, 15.09.2014, p. 913-922.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dimethylarginines

T2 - Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria

AU - Weinberg, Joe Brice

AU - Yeo, Tsin W.

AU - Mukemba, Jackson P.

AU - Florence, Salvatore M.

AU - Volkheimer, Alicia D.

AU - Wang, Hao

AU - Chen, Youwei

AU - Rubach, Matthew

AU - Granger, Donald L.

AU - Mwaikambo, Esther D.

AU - Anstey, Nicholas M.

PY - 2014/9/15

Y1 - 2014/9/15

N2 - Background: Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.Methods: We studied Tanzanian children ages 4–8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.Results: ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde­pendent­ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.Conclusions: In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children. 

AB - Background: Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown.Methods: We studied Tanzanian children ages 4–8 years with malaria. Plasma levels of arginine, arginase, cell-free hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured.Results: ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine:ADMA ratio normalized, but SDMA did not. Arginine:ADMA ratios, but not arginine, were significantly and inde­pendent­ly inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria.Conclusions: In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children. 

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KW - arginine

KW - arginine derivative

KW - dimethylarginine

KW - hemoglobin

KW - histidine

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KW - asymmetric dimethylarginine

KW - falciparum malaria

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KW - symmetric dimethylarginine

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KW - Child

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KW - Malaria, Falciparum

KW - Male

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DO - 10.1093/infdis/jiu156

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