title: Allergen-induced early and late asthmatic responses are not affected by inhibition of endogenous nitric oxide.
abstract: Endogenous exhaled nitric oxide (NO) is increased during the late response to inhaled allergen in patients with asthma and may be bronchoprotective in asthma or have a deleterious effect when generated in excess under inflammatory conditions. To investigate this, we evaluated the effect of inhibiting endogenous NO production with nebulized NG-nitro-L-arginine methyl ester (L-NAME), a nonselective NO synthase (NOS) inhibitor, on early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma. After a screening allergen challenge (AC), 22 male patients attended two visits conducted in a double-blind, randomized, placebo-controlled, crossover manner. Twelve patients demonstrating an early asthmatic response only (single responders) inhaled either L-NAME 170 mg or 0.9% saline 20 min before AC, with exhaled NO and FEV1 measured for 3 h. Ten patients demonstrating both early and late asthmatic responses (dual responders) were studied in a similar fashion but inhaled two further doses of L-NAME or placebo 3.5 and 7 h after the initial dose, with exhaled NO and FEV1 measured for 10 h. L-NAME reduced exhaled NO levels by 77 +/- 5% (p < 0.01) and 71 +/- 7% (p < 0.01) in single and dual responders, respectively, but had no significant effect on early or late asthmatic responses. Following AC in single responders, the mean (+/- SEM) maximum fall in FEV1 after L-NAME and saline was 21.2 +/- 2.9% and 23.8 +/- 3.0%, respectively, and in dual responders, 31.2 +/- 4.5% and 31.8 +/- 5. 8% during the early asthmatic responses, and 27.4 +/- 3.9% and 30.6 +/- 4.5% during the late asthmatic responses, respectively. Area under the curve (AUC) did not significantly differ. AUC0-2 h in single responders after L-NAME and saline was 20.2 +/- 3.9 and 24.9 +/- 4.4 Delta% FEV1/h, and in dual responders, 37.6 +/- 8.4 and 36.7 +/- 8.4 Delta% FEV1/h, respectively, and 106.2 +/- 18.9 and 117.1 +/- 22.4 Delta% FEV1/h, respectively, for the AUC4-10 h. This study suggests that in mild allergic asthma, endogenous NO neither protects against nor contributes to the processes underlying airway responses to inhaled allergen.
authors.affiliation: Royal Brompton Clinical Studies Unit, Department of Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Taylor
authors.forename: J L
authors.initials: JL
authors.lastname: McGrath
authors.forename: B J
authors.initials: BJ
authors.lastname: O'Connor
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester