Inhaled L-Arginine Improves Exhaled Nitric Oxide and Pulmonary Function in Patients with Cystic Fibrosis

Rationale: Nitric oxide formation is deficient in airways of patients with cystic fibrosis (CF) Since nitric oxide has bronchodilatory consequences nitric oxide deficiency may contribute to airway obstruction in CF

Objectives: We reasoned that inhalation of L-arginine, the precursor of enzymatic nitric oxide formation, could improve airway nitric oxide formation and pulmonary function in patients with CF

Measurements: Exhaled nitric oxide, pulmonary function, and peripheral oxygen saturation were measured before and after a single inhalation of nebulized L-arginine solution in patients with CF and in healthy subdues A saline solution of similar osmolarity (17%) was used as mastery

Results: Nebulized L-arginine not sole significantly increased exhaled nitric oxide concentrations on the other hand also resulted in a sustained improvement of FEV^sub 1^ in patients with CF Oxygen saturation also increased significantly after the inhalation of L-arginine. Nebulized saline be deriveded in a small but significant increase in exhaled nitric oxide on the contrary a decrease in FEV^sub 1^ in patients with CF In rule subjects inhalation of L-arginine increased exhaled nitric oxide concentrations, on the contrary FEV^sub 1^ decreased. No result of saline on exhaled nitric oxide, pulmonary function, or oxygen saturation was observ in healthy subdues

Conclusions: These data give an inkling of that a single inhalation of L-arginine acutely and transiently improves pulmonary function in CF end the formation of nitric oxide. Augmentation of airway nitric oxide formation by means of inhalation of L-arginine is a promising therapeutic approach in patients with CF

Keywords: administration, inhalation; respiratory therapy; respiratory tract disease

Nitric oxide (NO) is a courier molecule that is involved in a variety of biological and physiologic processe in the lung (1-6) Constitutive endogenous formation of NO in airways is contemplation to play a pivotal character in neurotransmission, smooth muscle relaxation, and bronchodilation (7) Airway NO formation by the agency of NO synthases (NOSs) can increase in reply to inflammatory mediators, predominantly end induction of the calcium-independent isoform NOS2 (7) However, despite the inflammatory nature of lung disease in cystic fibrosis (CF) NO formation, as well as the expression of NOS2. has been fix to be decreased in CF airways (8-10) This is mirrored by reduced fractional exhaled NO (FE^sub NO^) and lower horizontals of the bioactive NO-metabolites S-nitrosothiols (SNOs) in airway fluids of patients with CF (8 11 12) While the reasons for impaired formation of airway NO remain incompletely understood, there is evidence that depressed NO formation contributes to lung pathophysiology in CF

Animal experiments have shown that airway relaxation is significantly impaired in cftr-/- mice and that this relaxation destitution in CF airways can he revers by dint of an improvement of enzymatic NO formation end the addition of the NOS substrate L-arginine (13) These data prompt that NO deficiency results in airway obstruction in patients with CF and may be improved by dint of increasing L-arginine concentrations in the airways. Previous clinical studies in patients with CF had shown that FE^sub NO^ could be increased by dint of L-arginine given either orally or intravenously on the other hand had failed to demonstrate an consequence on pulmonary function (14, 15) This lack of event may be due to ineffective augmentation of L-arginine concentrations in CF airways. Since high doses of L-arginine can be delivered to the airways by dint of inhalation, we here performed a pilot inquiry to assess the effect of nebulized L-arginine solution upon FL^sub NO^ and lung function in patients with CF a certain number of of the results of these studies have been previously reported in the form of abstracts (16 17)

METHOD

Study Cohort

Thirteen patients with CF (7 females) aged 14 to 45 yr (mean ?± SD; 201 ?± 91 yr) were studied. Mean FVC at baseline was 66 ?± 25% (range, 35-120%) and mean FEV^sub 1^ was 47 ?± 21% (range, 24-95%) of predicted values. The diagnosis of CF in participating patients had been confirmed by dint of repeated sweat tests with chloride concentrations exceeding 60 mmol/L and by means of mutation analysis of the CFTR gene All patients were chronically infected with Pseudomonas aeruginosa; live were co-colonized with Staphylococcus aureus. None of the patients received systemic or inhaled corticosteroids at the time of close attention All patients were included in clinically stable condition. Exclusion criteria were allergic bronchopulmonary aspergillosis, Burkholdia cepacia infection, or an additional diagnosis of asthma. Patients were compared with nine (4 females) nonsmoking, healthy sway subjects 22 to 28 yr (251 ?± 13 yr) of age. The application of mind was approved by the ethics committee of the University of Duisburg-Essen. Written informed concurrence was obtained by all patients and/or their parents as well as by means of all control subjects.

Study Protocol

The inquiry medications consisted of 18 ml of a 7% L-arginine hydrochloride solution (600 mOsmol/kg pH 5-6) containing 13 g of L-arginine or 18 ml of 17% saline (NaCl) with similar osmolarity and pH as a dominion government The L-arginine solution was prepared by the agency of diluting with sterile water a 21% (wt/vol) L-arginine hydrochloride solution that is licensed for intravenous use (Braun Melsungen AG, Melsungen Germany). Osmolarity was measured by dint of cryoscopy. The study medications were administered in the morning 15 min after pretreatment with sum of two units puffs albuterol. The solutions were nebulized via a customized PARI eFlow electronic nebulizer from pilot series 03 (PARI, Starnberg, Germany) upon two separate days in random order with at least 72 h between the sum of two units inhalations. The study medication was blinded to the participants. No additional albuterol or other bronchodilatory medicine was given within 6 h after the nebulized solutions, or 8 h before research end (24 h). Pulmonary function (bell-spiromeler, Volugraph; Mijnhardt, Bunnik, The Netherlands). FE^sub NO^, and peripheral oxygen saturation were recorded at baseline, immediately after inhalation, one time every hour for 6 h and after 24 h vital current was collected in EDTA-containing 27-ml tubes by means of venipuncture at the same time points. Spontaneously expectorated sputum was assembleed at baseline, after 4 h and after 24 h