Vol. 283, Issue 2, 788-793, 1997

Bronchoconstrictor and Respiratory Effects of Neurokinin A in Dogs

Joseph E. Sherwood, Peter J. Mauser and Richard W. Chapman

Department of Allergy, Schering-Plough Research Institute, Kenilworth, New Jersey

Neurokinin A (NKA) is the primary bronchoconstrictor tachykinin in the lungs of several species, including humans and has been implicated as an important mediator of inflammatory lung disorders, such as asthma. In this study, we investigated the effect of NKA on airway mechanics (lung resistance, dynamic lung compliance) and respiration (tidal volume, respiratory rate) in anesthetized, spontaneously breathing, male beagle dogs. The dogs were challenged with aerosolized NKA that was delivered from a jet nebulizer to the airways through an endotracheal tube. The challenge consisted of five separate inflations of 600 ml of air/inflation over a 1-min period. Challenge with aerosolized NKA (0.1-1%) produced a dose-dependent increase in lung resistance and a decrease in dynamic lung compliance. The bronchoconstriction induced by 1% NKA peaked at 0.5 min after challenge and had a duration of approximately 5 min. Challenge with 1% NKA also reduced tidal volume and increased respiratory rate. Pretreatment of dogs with the NK-₂ receptor antagonist, SR 48968 dose-dependently (1-10 mg/kg, p.o.) blocked the bronchoconstriction and respiratory responses to NKA challenge. Pretreatment with the NK₁-receptor antagonist, CP 99994 (1 mg/kg, i.v.) had no effect on the increase in lung resistance and the decrease in dynamic lung compliance due to NKA challenge, but blunted the respiratory response to NKA. Pretreatment of dogs with inhaled ipratropium bromide (0.01%) slightly, but significantly reduced the increase in lung resistance due to NKA challenge but had no effect on the decrease of dynamic lung compliance or on the respiratory responses to NKA. As expected, the bronchoconstrictor response to inhaled methacholine was completely blocked by inhaled ipratropium bromide (0.01%). In conclusion, we have identified an NK₂-receptor mediated bronchoconstrictor effect of NKA in dogs. Cholinergic reflexes play a small, but significant role in this response. Furthermore, both NK₁ and NK₂-receptors appear to be involved with the development of the rapid, shallow breathing response to NKA challenge. These results demonstrate an effect of tachykinins on airway mechanics and ventilatory reflexes in dogs.