Effect of bradykinin on allergen induced increase in exhaled nitric oxide in asthma

Background: Exposure of patients with atopic asthma to allergens produces a long term increase in exhaled nitric oxide (FENO), probably reflecting inducible NO synthase ( NOS) expression. In contrast, bradykinin (BK) rapidly reduces FENO. It is unknown whether BK suppresses increased FENO production after allergen exposure in asthma, and whether it modulates FENO via NOS inhibition. Methods: Levels of FENO in response to aerosolised BK were studied before ( day 3) and 48 hours after (day 10) randomised diluent (diluent/placebo/ BK (Dil/P/BK)), allergen (allergen/placebo/BK(All/ P/ BK), and allergen/L-NMMA/BK ( All/ L/BK)) challenges ( day 8) in 10 atopic, steroid naive, mild asthmatic patients with dual responses to inhaled house dust mite extract. To determine whether BK modulates FENO via NOS inhibition, subjects performed pre- and post-allergen BK challenges after pretreatment with the NOS inhibitor L-NMMA in the All/ L/BK period. Results: Allergen induced a fall in FENO during the early asthmatic reaction ( EAR) expressed as AUC(0-1) ( ANOVA, p = 0.04), which was followed by a rise in FENO during the late asthmatic reaction (LAR) expressed as AUC(1-48) (ANOVA, p = 0.008). In the Dil/P/BK period, FENO levels after BK on pre- and post-diluent days were lower than FENO levels after placebo ( difference 23.5 ppb (95% CI 6.2 to 40.9) and 22.5 ppb ( 95% CI 7.3 to 37.7), respectively; p<0.05). Despite the long lasting increase in FENO following allergen challenge in the LAR, BK suppressed FENO levels at 48 hours after allergen challenge in the All/ P/ BK period, lowering the increased FENO ( difference from placebo 54.3 ppb ( 95% CI 23.8 to 84.8); p = 0.003) to the baseline level on the pre- allergen day ( p = 0.51). FENO levels were lower after L-NMMA than after placebo on pre- allergen ( difference 10.85 ppb ( 95% CI 1.3 to 20.4); p = 0.03) and post-allergen ( difference 36.2 ppb ( 95% CI 5.5 to 66.9); p = 0.03) days in the All/ L/BK and All/ P/ BK periods, respectively. L-NMMA did not significantly potentiate the pre- and post-allergen reduction in BK induced FENO. Conclusions: Bradykinin suppresses the allergen induced increase in exhaled NO in asthma; this is not potentiated by L-NMMA. Bradykinin and L-NMMA may follow a common pathway in reducing increased NO production before and after experimental allergen exposure. Reinforcement of this endogenous protective mechanism should be considered as a therapeutic target in asthma.