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.
    @article{45cf5374899c49de9456eca5b2d09324,
    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. ",
    keywords = "6 n,n' dimethylarginine, angiopoietin 2, arginase, arginine, arginine derivative, dimethylarginine, hemoglobin, histidine, histidine rich protein 2, lactic acid, n(g),n(g) dimethylarginine, nitric oxide, unclassified drug, adult, amino acid blood level, amino acid synthesis, article, bioavailability, brain malaria, child, controlled study, disease severity, enzyme blood level, female, hemoglobin blood level, human, human cell, hypoargininemia, major clinical study, malaria falciparum, male, priority journal, Tanzania, urea cycle disorder, angiopoeitin 2, asymmetric dimethylarginine, falciparum malaria, lactate, symmetric dimethylarginine, Acute Disease, Arginase, Arginine, Case-Control Studies, Child, Child, Preschool, Female, Hemoglobins, Humans, Malaria, Falciparum, Male, Nitric Oxide",
    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.}",
    year = "2014",
    month = "9",
    day = "15",
    doi = "10.1093/infdis/jiu156",
    language = "English",
    volume = "210",
    pages = "913--922",
    journal = "Journal of Infectious Diseases",
    issn = "0022-1899",
    publisher = "Oxford University Press",
    number = "6",

    }

    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. 

    KW - 6 n,n' dimethylarginine

    KW - angiopoietin 2

    KW - arginase

    KW - arginine

    KW - arginine derivative

    KW - dimethylarginine

    KW - hemoglobin

    KW - histidine

    KW - histidine rich protein 2

    KW - lactic acid

    KW - n(g),n(g) dimethylarginine

    KW - nitric oxide

    KW - unclassified drug

    KW - adult

    KW - amino acid blood level

    KW - amino acid synthesis

    KW - article

    KW - bioavailability

    KW - brain malaria

    KW - child

    KW - controlled study

    KW - disease severity

    KW - enzyme blood level

    KW - female

    KW - hemoglobin blood level

    KW - human

    KW - human cell

    KW - hypoargininemia

    KW - major clinical study

    KW - malaria falciparum

    KW - male

    KW - priority journal

    KW - Tanzania

    KW - urea cycle disorder

    KW - angiopoeitin 2

    KW - asymmetric dimethylarginine

    KW - falciparum malaria

    KW - lactate

    KW - symmetric dimethylarginine

    KW - Acute Disease

    KW - Arginase

    KW - Arginine

    KW - Case-Control Studies

    KW - Child

    KW - Child, Preschool

    KW - Female

    KW - Hemoglobins

    KW - Humans

    KW - Malaria, Falciparum

    KW - Male

    KW - Nitric Oxide

    UR - http://www.scopus.com/inward/record.url?scp=84906754006&partnerID=8YFLogxK

    U2 - 10.1093/infdis/jiu156

    DO - 10.1093/infdis/jiu156

    M3 - Article

    VL - 210

    SP - 913

    EP - 922

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 6

    ER -