Nitric oxide is generated in smooth muscle layer by neurokinin A and counteracts constriction in guinea pig airway

It has been reported that several bronchoconstrictors generate nitric oxide (NO), counteracting bronchoconstriction, and removal of bronchial epitheli a reduces NO production. However, it has not been elucidated whether neurok inin A (NKA), a potent bronchoconstrictor liberated from nerve terminals, g enerates NO. Specific questions in this study were (1) does NKA also genera te NO, (2) does NO counteract NKA-induced bronchoconstriction, and (3) does the NO generation require bronchial epithelial cells? In an in vivo study exogenous as well as endogenous (capsaicin-induced) NKA increased airway op ening pressure (P-ao) and the exhaled NO level, and both were inhibited by an antagonist selective for NK2 receptor (a receptor for NKA), SR48968. The exhaled NO level became negligible with an inhibitor of NO synthase (NOS) type 1-3 (N-G-nitro-L-arginine methyl ester, L-NAME) with increased P-ao, b ut not with a NOS type 2 inhibitor. In an in vitro study, NKA increased the nitrite/nitrate level in superfused fluid of tracheal segments. Removing s mooth muscle reduced nitrite/nitrate in the fluid to negligible levels, whi le the level was unchanged with removal of the epithelia. Pretreatment with L-NAME enhanced the tension of epithelia-removed tracheal segments. These findings indicate that (1) NKA generates NO, (2) NO counteracts NKA-induced bronchoconstiriction, and (3) NKA activates NOS in the muscle layer, indep endently of bronchial epithelia. (C) 2001 Academic Press.