Effect of tachykinins in small human airways

We have compared the contractile responses of substance P (SP) and neurokinin A (NKA) to that of the non degradable muscarinic agonist, carbachol, in small and large human airways in vitro. We have also investigated the effects of the neutral endopeptidase (NEP) inhibitor, thiorphan (100 microM) on these responses. NKA contracted large and small airways to a different extent (56% vs 92% of carbachol maximal contraction, respectively). NKA was significantly less potent in large vs small bronchi (EC50 = 150 +/- 15 vs 12 +/- 5 nM respectively, p less than 0.05). SP had a lower contractile effect in large (26% carbachol maximum) and small airways (59%) with EC50 values higher than 0.5 microM. The enkephalinase inhibitor thiorphan shifted the concentration-response curve to NKA to the left in large (EC50 = 35.2 +/- 8.2 nM) and small bronchi (EC50 = 2.8 +/- 1.3 nM, p less than 0.02). This shift was associated with an increase in the maximal contraction to NKA (75% in large vs 123% in small bronchi). The amplitude of contraction to SP was also potentiated in large (45%) and in smaller bronchi (101%). In conclusion, we have demonstrated that NKA has a significantly greater constrictor effect than a cholinergic agent in more peripheral human airways in vitro. This suggests that non cholinergic constrictor pathways are more likely to be important in more peripheral airways.