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.
Background-Nitric oxide (NO) may be bronchoprotective in asthma, possibly due to a direct action on airway smooth muscle or through mast cell stabilisation. To investigate this the eVects of two doses of nebulised N G -nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), an indirect spasmogen which activates mast cells, were evaluated in patients with mild asthma. Methods-The study consisted of two phases each with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studied in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaled L-NAME in a dose of 170 mg or 0.9% saline before being challenged with histamine and AMP. Results-The mean (95% CI) reduction in exhaled NO levels after L-NAME 54 mg was 78% (66 to 90) but this did not alter airway responsiveness; the geometric mean (SE) concentration provoking a fall of 20% or more in forced expiratory volume in one second (PC 20 ) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast, L-NAME 170 mg reduced NO levels to a similar extent (81% (95% CI 76 to 87)) but increased airway responsiveness by approximately one doubling dose to both spasmogens; the geometric mean (SE) PC 20 for histamine after L-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p<0.001), and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively (p<0.001). Conclusions-These results suggest that L-NAME increases airway responsiveness in asthma. This may occur through mechanisms separate from NO inhibition or through pathways independent of those responsible for production of NO measured in exhaled air. (Thorax 1998;53:483-489)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.