Dimethylarginines: Endogenous Inhibitors of Nitric Oxide Synthesis in Children With Falciparum Malaria

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.