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

1 The tachykinin, neurokinin A (NKA), contracts guinea-pig airways both in vitro and in vivo, preferentially activating smooth muscle NK2 receptors, a lthough 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 s elective NK1 receptor agonists have been reported to activate both smooth m uscle and epithelial NK1 receptors, however septide appears only to activat e smooth muscle NK1 receptors. 2 The aim of the present study was to investigate whether NMA-induced bronc hoconstriction in guinea-pigs in vivo may be limited by NO release via NK1 receptor activation, and whether selective NK1 receptor agonists may activa te this mechanism differently. 3 Aerosolized NKA caused an increase in total pulmonary resistance (RL) tha t was markedly reduced by the NK2 receptor antagonist, SR 48968, and abolis hed by the combination of SR 48968 and the NK1 receptor antagonist, CF-99,9 94. The increase in RL evoked by NKA was potentiated by pretreatment with t he 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 b y L-Arginine, but not by D-Arginine. 4 Pretreatment with L-NAME did not affect the increase in RL induced by the selective NK2 receptor agonist, [beta-Ala(8)]NKA(4-10), and by the selecti ve NK1 receptor agonist, septide, whereas it markedly potentiated the incre ase in RL caused by a different NK1 selective agonist, [Sar(9),Met(O-2)(11) ]SP. Dose-response curves showed that septide was a more potent bronchocons trictor than [Sar(9),Met(O-2)(11)]SP to cause bronchoconstriction. 5 Pretreatment with the NK1 receptor antagonist, CP-96,994, abolished the a bility of L-NAME to increase bronchoconstriction to aerosolized! NKA. Bronc hoconstriction to aerosolized NKA was increased by L-NAME, after pretreatme nt with the NK3 receptor antagonist, SR 142801. 6 The present study shows that ill 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 i s apparently insensitive to septide, thus justifying, It least in part, the high potency of septide to cause bronchoconstriction in guinea-pigs.