L-Citrulline increases nitric oxide and improves control in obese asthmatics

JCI Insight. 2019 Dec 19;4(24):e131733. doi: 10.1172/jci.insight.131733.


BACKGROUNDThe airways of obese asthmatics have been shown to be NO deficient, and this contributes to airway dysfunction and reduced response to inhaled corticosteroids. In cultured airway epithelial cells, L-citrulline, a precursor of L-arginine recycling and NO formation, has been shown to prevent asymmetric dimethyl arginine-mediated (ADMA-mediated) NO synthase (NOS2) uncoupling, restoring NO and reducing oxidative stress.METHODSIn a proof-of-concept, open-label pilot study in which participants were analyzed before and after treatment, we hypothesized that 15 g/d L-citrulline for 2 weeks would (a) increase the fractional excretion of NO (FeNO), (b) improve asthma control, and (c) improve lung function. To this end, we recruited obese (BMI >30) asthmatics on controller therapy, with a baseline FeNO of ≤30 ppb from the University of Colorado Medical Center and Duke University Health System.RESULTSA total of 41 subjects with an average FeNO of 17 ppb (95% CI, 15-19) and poorly controlled asthma (average asthma control questionnaire [ACQ] 1.5 [95% CI, 1.2-1.8]) completed the study. Compared with baseline, L-citrulline increased whereas ADMA and arginase concentration did not (values represent the mean Δ and 95% CI): plasma L-citrulline (190 μM, 84-297), plasma L-arginine (67 μM, 38-95), and plasma L-arginine/ADMA (ratio 117, 67-167). FeNO increased by 4.2 ppb (1.7-6.7 ppb); ACQ decreased by -0.46 (-0.67 to 0.27 points); the forced vital capacity and forced exhalation volume in 1 second, respectively, changed by 86 ml (10-161 ml) and 52 ml (-11 to 132 ml). In a secondary analysis, the greatest FEV1 increments occurred in those subjects with late-onset asthma (>12 years) (63 ml [95% CI, 1-137]), in females (80 ml [95% CI, 5-154]), with a greater change seen in late-onset females (100 ml, [95% CI, 2-177]). The changes in lung function or asthma control were not significantly associated with the changes before and after treatment in L-arginine/ADMA or FeNO.CONCLUSIONShort-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in those with late-onset asthma and in females.TRIAL REGISTRATIONClinicalTrials.gov NCT01715844.FUNDINGNIH NHLBI R01 HL146542-01.

Keywords: Asthma; Pulmonology.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Arginine / analogs & derivatives
  • Arginine / blood
  • Asthma / blood
  • Asthma / complications
  • Asthma / diagnosis
  • Asthma / diet therapy*
  • Citrulline / administration & dosage*
  • Citrulline / blood
  • Dietary Supplements*
  • Female
  • Forced Expiratory Volume
  • Humans
  • Male
  • Middle Aged
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Obesity / blood
  • Obesity / complications
  • Obesity / diet therapy*
  • Oxidative Stress / drug effects
  • Pilot Projects
  • Proof of Concept Study
  • Severity of Illness Index
  • Treatment Outcome
  • Young Adult


  • Citrulline
  • Nitric Oxide
  • N,N-dimethylarginine
  • Arginine
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II

Associated data

  • ClinicalTrials.gov/NCT01715844