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

1 In the present study, the roles of nitric oxide (NO) and superoxide anions (O-2(-)) in allergen-induced air-way hyperreactivity (AHR) after the late asthmatic reaction (LAR) were investigated ex vivo, by examining the effects of the NO synthase inhibitor N-omega-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. 2 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. 3 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 Delta pEC(50)) (EL-IL), as a measure of epithelial integrity, was unchanged. 4 In the presence of L-NAME (100 muM, 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). 5 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). 6 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.