Allergen-induced Early and Late Asthmatic Responses Are Not Affected by Inhibition of Endogenous Nitric Oxide

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 N G-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 Δ % FEV1/h, and in dual responders, 37.6 ± 8.4 and 36.7 ± 8.4 Δ % FEV1/h, respectively, and 106.2 ± 18.9 and 117.1 ± 22.4 Δ % 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.