A pilot study of a non-invasive oral nitrate stable isotopic method suggests that arginine and citrulline supplementation increases whole-body NO production in Tanzanian children with sickle cell disease

• Published in: Nitric oxide 2018-04, Vol.74, p.19-22
• Main Authors: Marealle, Alphonce I., Siervo, Mario, Wassel, Sara, Bluck, Les, Prentice, Andrew M., Minzi, Omary, Sasi, Philip, Kamuhabwa, Appolinary, Soka, Deogratias, Makani, Julie, Cox, Sharon E.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Anemia, Sickle Cell - metabolism; Arginine - administration & dosage; Arginine - pharmacology; Child; Citrulline - administration & dosage; Citrulline - pharmacology; Dietary Supplements; Female; Humans; Male; Nitrates - administration & dosage; Nitrates - metabolism; Nitric Oxide - biosynthesis; Nitrogen Isotopes; Pilot Projects; Tanzania
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2017.12.009

Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell disease (SCD). We designed a nested pilot study to be conducted within a clinical trial testing the effects of a daily ready-to-use supplementary food (RUSF) fortified with arginine (Arg) and citrulline (Citr) vs. non-fortified RUSF in children with SCD. The pilot study evaluated 1) the feasibility of a non-invasive stable isotope method to measure whole-body NO production and 2) whether Arg+Citr supplementation was associated with increased whole-body NO production. Twenty-nine children (70% male, 9–11years, weight 16.3–31.3 kg) with SCD. Sixteen children received RUSF+Arg/Citr (Arg, 0.2  g/kg/day; Citr, 0.1  g/kg/day) in combination with daily chloroquine (50 mg) and thirteen received the base RUSF in combination with weekly chloroquine (150 mg). Plasma amino acids were assessed using ion-exchange elution (Biochrom-30, Biochrom, UK) and whole-body NO production was measured using a non-invasive stable isotopic method. The RUSF+Arg/Citr intervention increased plasma arginine (P = .02) and ornithine (P = .003) and decreased the ratio of asymmetric dimethylarginine to arginine (P = .01), compared to the base RUSF. A significant increase in whole-body NO production was observed in the RUSF-Arg/Citr group compared to baseline (weight-adjusted systemic NO synthesis 3.38 ± 2.29 μmol/kg/hr vs 2.35 ± 1.13 μmol/kg/hr, P = .04). No significant changes were detected in the base RUSF group (weight-adjusted systemic NO synthesis 2.64 ± 1.14 μmol/kg/hr vs 2.53 ± 1.12 μmol/kg/hr, P = .80). The non-invasive stable isotopic method was acceptable and the results provided supporting evidence that Arg/Citr supplementation may increase systemic NO synthesis in children with SCD. •This method for measuring whole-body NO synthesis is feasible in young children.•The isotopic decay of the stable isotope tracer demonstrated good linear fit.•Arginine and citrulline supplementation may increase whole-body NO synthesis.