Role of nitric oxide and superoxide in allergen‐induced airway hyperreactivity after the late asthmatic reaction in guinea‐pigs

In the present study, the roles of nitric oxide (NO) and superoxide anions (O 2 − ) in allergen‐induced airway hyperreactivity (AHR) after the late asthmatic reaction (LAR) were investigated ex vivo , by examining the effects of the NO synthase inhibitor N ω ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME) and superoxide dismutase (SOD) on the responsiveness to methacholine of isolated perfused guinea‐pig treacheae from unchallenged (control) animals and from animals 24 h after ovalbumin challenge. At 24 h after allergen challenge, the animals developed AHR in vivo , as indicated by a mean 2.63±0.54 fold ( P <0.05) increase in sensitivity to histamine inhalation. Compared to unchallenged controls, tracheal preparations from the ovalbumin‐challenged guinea‐pigs displayed a significant 1.8 fold ( P <0.01) increase in the maximal response (E max ) to methacholine, both after intraluminal (IL) and extraluminal (EL) administration of the agonist. No changes were observed in the sensitivity (pEC 50 ) to the agonist. Consequently, the ΔpEC 50 (EL‐IL), as a measure of epithelial integrity, was unchanged. In the presence of L ‐NAME (100 μ M , IL), tracheae from control guinea‐pigs showed a 1.6 fold ( P <0.05) increase in the E max of IL methacholine. By contrast, the E max of IL methacholine was significantly decreased in the presence of 100 u ml −1 EL SOD (54% of control, P <0.01). Remarkably, the increased responsiveness to IL methacholine at 24 h after allergen challenge was reversed by L ‐NAME to control ( P <0.01), and a similar effect was observed with SOD ( P <0.01). The results indicate that both NO and O 2 − are involved in the tracheal hyperreactivity to methacholine after the LAR, possibly by promoting airway smooth muscle contraction through the formation of peroxynitrite.British Journal of Pharmacology (2001) 133 , 1235–1242; doi: 10.1038/sj.bjp.0704191