Role of nitric oxide and septide‐insensitive NK1 receptors in bronchoconstriction induced by aerosolised neurokinin A in guinea‐pigs

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Abstract
The tachykinin, neurokinin A (NKA), contracts guinea‐pig airways both in vitro and in vivo, preferentially activating smooth muscle NK2 receptors, although smooth muscle NK1 receptors may also contribute. In vitro evidence suggests that NKA activates epithelial NK1 receptors, inducing the release of nitric oxide (NO) and subsequent smooth muscle relaxation. A number of selective NK1 receptor agonists have been reported to activate both smooth muscle and epithelial NK1 receptors, however septide appears only to activate smooth muscle NK1 receptors. The aim of the present study was to investigate whether NKA‐induced bronchoconstriction in guinea‐pigs in vivo may be limited by NO release via NK1 receptor activation, and whether selective NK1 receptor agonists may activate this mechanism differently. Aerosolized NKA caused an increase in total pulmonary resistance (RL) that was markedly reduced by the NK2 receptor antagonist, SR 48968, and abolished by the combination of SR 48968 and the NK1 receptor antagonist, CP‐99,994. The increase in RL evoked by NKA was potentiated by pretreatment with the NO synthase (NOs) inhibitor, L‐NAME, but not by the inactive enantiomer D‐NAME. Potentiation by L‐NAME of NKA‐induced increase in RL was reversed by L‐Arginine, but not by D‐Arginine. Pretreatment with L‐NAME did not affect the increase in RL induced by the selective NK2 receptor agonist, [β‐Ala8]NKA(4‐10), and by the selective NK1 receptor agonist, septide, whereas it markedly potentiated the increase in RL caused by a different NK1 selective agonist, [Sar9,Met(O2)11]SP. Dose‐response curves showed that septide was a more potent bronchoconstrictor than [Sar9,Met(O2)11]SP to cause bronchoconstriction. Pretreatment with the NK1 receptor antagonist, CP‐96,994, abolished the ability of L‐NAME to increase bronchoconstriction to aerosolized NKA. Bronchoconstriction to aerosolized NKA was increased by L‐NAME, after pretreatment with the NK3 receptor antagonist, SR 142801. The present study shows that in vivo bronchoconstriction in response to the aerosolized naturally occurring tachykinin, NKA, is limited by its own ability to release relaxant NO via NK1 receptor activation. This receptor is apparently insensitive to septide, thus justifying, at least in part, the high potency of septide to cause bronchoconstriction in guinea‐pigs. British Journal of Pharmacology (2000) 129, 915–920; doi:10.1038/sj.bjp.0703135