Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma

Abstract

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 effects 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 inhaledl-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 (PC₂₀) 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) PC₂₀ for histamine after l-NAME 170 mg and saline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (pCONCLUSIONS These results suggest thatl-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.