Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma.
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 NG-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 (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 (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.
Department of Thoracic Medicine, Imperial College School of Medicine, National Heart and Lung Institute, London, UK.
D A
DA
Taylor
J L
JL
McGrath
L M
LM
Orr
P J
PJ
Barnes
B J
BJ
O'Connor
D000249:Adenosine Monophosphate; D000280:Administration, Inhalation; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001944:Breath Tests; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D006632:Histamine; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000032:analysis / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D000249:Adenosine Monophosphate; D006632:Histamine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester