Age-Related Changes of Urinary Nitrite/Nitrate Excretion in Normal Children

Tsukahara, Hirokazu; Hiraoka, Masahiro; Hori, Chikahide; Miyanomae, Takeshi; Kikuchi, Kiyoshi; Sudo, Masakatsu

doi:10.1159/000190196

Cited by 23 publications

(14 citation statements)

References 9 publications

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“…However, multiple regression analysis showed age as the only predictor variable of whole-body NO synthesis, suggesting that normal aging modulates NO homeostasis in children. This finding agrees with other independent research groups who reported high levels of urinary nitrate excretion (index of NO synthesis) in infancy that declined with age (35)(36)(37). A similar age-related decrease was also observed in plasma (6,37) and cerebrospinal fluid nitrate concentrations (38).…”

Section: Subjectssupporting

confidence: 92%

A Noninvasive, Sensitive, Specific, and Reliable Approach to Assess Whole-Body Nitric Oxide Synthesis in Children

2006

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Determination of nitric oxide (NO) synthesis in vivo is essential to understand the pathophysiologic role and therapeutic implications of the L-arginine/NO pathway in pediatric diseases. The aim of this study was to establish a noninvasive, sensitive, specific, and reliable approach to determine whole-body NO synthesis in healthy children. Seventeen healthy children (eight boys/nine girls, 4 -16 y) were studied twice, and six of them on three occasions. Fasting children received a single oral dose of nonradioactive T he L-arginine/NO pathway has been an exciting research area for the past two decades. NO is endogenously synthesized from the amino acid L-arginine by NO synthase (NOS) in numerous cells, including platelets, neurons, macrophages, and endothelial cells (1). Three isoforms of human NOS have been cloned: neuronal, endothelial, and inducible (2). Both the neuronal NOS and endothelial NOS are constitutively expressed in cells and produce picomolar amounts of NO. By contrast, the inducible isoform produces high and sustained levels of NO and is usually expressed in macrophages and vascular smooth muscle cells following the exposure to cytokines and lipopolysaccharide (3). The physiologic importance of the L-arginine/NO pathway has been extensively studied in humans. It is known to play a major role in controlling vascular tone, platelet function, neurotransmission, and bronchial airway reactivity (1,4).Basic research on NO derived from in vitro and in vivo experimental models has started to have an impact on pediatrics. Accumulating evidence suggest that the NO signaling pathway is abnormal in a number of pediatric conditions including primary pulmonary hypertension (5), childhood essential hypertension (6), and cerebral malaria (7) and markedly increased in others such as septic shock (8), gastroenteritis (9,10), bronchial asthma (11), type 1 diabetes mellitus (12), and autoimmune and inflammatory diseases (13). Accurate and reliable determination of NO synthesis in vivo is essential to understand the pathophysiologic and therapeutic roles of this biologic pathway. Direct measurement of exhaled NO is a noninvasive and practical approach for assessing airway inflammation in children (14). Indeed, exhaled NO has been proposed as a tool for screening and monitoring airway inflammation and titration of anti-inflammatory therapy in asthmatic children (15). On the other hand, determination of systemic NO synthesis has been proved difficult because of NO's short plasma half-life (3-5 s) (16). This limitation has led to the development of functional and chemical markers to determine NO bioactivity. Biomarkers such as cyclic guanosine monophosphate, L-citrulline, and nitrate concentrations in plasma and urine have been used in clinical studies to assess systemic NO synthesis. However, these metabolites are not specific for the L-arginine/NO pathway (17). An approach to assess whole-body NO synthesis in critically ill children (i.e. septic shock) consists of a primed, 5-8-h constant i.

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Section: Subjectssupporting

confidence: 92%

A Noninvasive, Sensitive, Specific, and Reliable Approach to Assess Whole-Body Nitric Oxide Synthesis in Children

2006

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“…In two studies of nonfasting Japanese children in non-malaria endemic areas, 15,16 urine NOx excretion was highest in infancy, decreasing progressively with age. A similar age-related decrease has been found with cerebrospinal fluid NOx concentrations in European children.…”

Section: Discussionmentioning

confidence: 99%

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Anstey¹,

Weinberg²,

Wang³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.Nitric oxide (NO) mediates a diverse array of physiologic and pathologic processes, and appears to be an important mediator of the protective immune response to all stages of Plasmodium infections. 1 We have recently shown in Tanzanian children that systemic NO production and mononuclear cell (MNC) expression of the inducible isoform of NO synthase (NOS2) are inversely related to malaria disease severity. Although suppressed in cerebral malaria, systemic NO production/MNC NOS2 expression was universally increased in healthy, asymptomatic malaria-exposed children with or without parasitemia.2 Nitric oxide production/MNC NOS2 expression was higher in those asymptomatic children with parasitemia found on thick film examination, suggesting that NO production in these children may in part be due to the known ability of parasites to induce macrophage NOS activity.3,4 However, the majority of the asymptomatic children with constitutive expression of NOS2 were thick film negative, raising the possibility that NOS2 expression was due to parasitemia below the detection limits of microscopy, subclinical infection with other pathogens, or age-related physiologic NOS2 expression in childhood.Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. [5][6][7] Because NO production has been linked with host protection in ...

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“…These observations may be related to age-related difference in NO production (Kissin et al, 1997;Tsukahara et al, 1997;Anstey et al, 1999b). Our recent studies in Tanzanian children show that NO production is highest in infancy, falling after the first year of life, then rising again after 5 years of age (Anstey et al, 1999b).…”

Section: Age Related Changes In No Production and Clinical Immunitymentioning

confidence: 91%

Nitric Oxide in Malaria

Anstey

Weinberg

Granger

2002

Nitric Oxide and Infection

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Age-Related Changes of Urinary Nitrite/Nitrate Excretion in Normal Children

Cited by 23 publications

References 9 publications

A Noninvasive, Sensitive, Specific, and Reliable Approach to Assess Whole-Body Nitric Oxide Synthesis in Children

A Noninvasive, Sensitive, Specific, and Reliable Approach to Assess Whole-Body Nitric Oxide Synthesis in Children

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Nitric Oxide in Malaria

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