Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma.
BACKGROUND
Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma.


METHODS
The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants.


RESULTS
The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine.


CONCLUSIONS
The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.
Ricciardolo
F L
FL
Institute of Respiratory Disease, University of Catanla, Italy.
Geppetti
P
P
Mistretta
A
A
Nadel
J A
JA
Sapienza
M A
MA
Bellofiore
S
S
Di Maria
G U
GU
D000328:Adult; D000336:Aerosols; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001920:Bradykinin; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008176:Lung Volume Measurements; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine
D000336:Aerosols; D004791:Enzyme Inhibitors; D016210:Methacholine Chloride; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D001920:Bradykinin