EFFECT OF ENDOGENOUS NITRIC-OXIDE INHIBITION ON AIRWAY RESPONSIVENESSTO HISTAMINE AND ADENOSINE-5'-MONOPHOSPHATE IN ASTHMA

Background-Nitric oxide (NO) may be bronchoprotective in asthma, possi bly due to a direct action on airway smooth muscle or through mast cel l stabilisation. To investigate this the effects of two doses of nebul ised N-G-nitro-L-arginine methyl ester (L-NAME), a non-selective NO sy nthase (NOS) inhibitor, on exhaled NO levels and airway responsiveness to histamine, a direct smooth muscle spasmogen, and adenosine-5'-mono phosphate (AMP), an indirect spasmogen which activates mast cells, wer e 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 studie d in a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhal ed L-NAME in a dose of 170 mg or 0.9% saline before being challenged w ith 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 provokin g a fall of 20% or more in forced expiratory volume in one second (PC, ,) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, resp ectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectiv ely, for AMP. In contrast, L-NAME 170 mg reduced NO levels to a simila r extent (81% (95% CI 76 to 87)) but increased airway responsiveness b y approximately one doubling dose to both spasmogens; the geometric me an (SE) PC20 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-Thes e results suggest that L-NAME increases airway responsiveness in asthm a. This may occur through mechanisms separate from NO inhibition or th rough pathways independent of those responsible for production of NO m easured in exhaled air.