Asymmetric Dimethylarginine Contributes to Airway Nitric Oxide Deficiency in Patients with Cystic Fibrosis

Rationale Airway nitric oxide is reduced in cystic fibrosis airways. Asymmetric dimethylarginine is an endogenous nitric oxide synthase inhibitor that may contribute to nitric oxide deficiency in cystic fibrosis. Objectives: To test the hypothesis that asymmetric dimethylarginine is increased in cystic fibrosis and contributes to nitric oxide deficiency and airway obstruction. Methods: The concentrations of asymmetric dimethylarginine, symmetric dimethylarginine, and L-arginine were measured in sputum of clinically stable patients with cystic fibrosis, in patients with cystic fibrosis before and after treatment for a pulmonary exacerbation, and in healthy control subjects, using liquid chromatography-tandem mass spectrometry. Measurements and Main Results: Asymmetric dimethylarginine was increased in cystic fibrosis compared with control sputum, and the L-arginine/asymmetric dimethylarginine ratio was decreased. Symmetric dimethylarginine exceeded asymmetric dimethylarginine concentrations in control sputum, but this ratio was reversed in cystic fibrosis. Treatment for pulmonary exacerbation resulted in a decrease in sputum asymmetric dimethylarginine and an improved L-arginine/asymmetric dimethylarginine ratio. The treatment-related decrease in asymmetric dimethylarginine correlated significantly with an increase in sputum nitric oxide metabolites and improvement in pulmonary function. The activity of the asymmetric dimethylarginine-metabolizing enzyme, dimethylarginine dimethylaminohydrolase, was higher in cystic fibrosis sputum before rather than after treatment, suggesting that the accumulation of asymmetric dimethylarginine is caused by increased production, not decreased degradation, of asymmetric dimethylarginine. Conclusions: Asymmetric dimethylarginine is increased in cystic fibrosis airways and may contribute to airway obstruction in patients with cystic fibrosis by reducing nitric oxide formation.