Relationship between airway responsiveness to neurokinin A and methacholine in asthma

Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma. To this end, we analyzed baseline data of 27 subjects with mild persistent asthma (20F/7M) 19-46 y; FEV1 81-136% pred.; PC20FEV1 (M)<80 μmol/mL) participating in a proof-of-concept study. All subjects were non-smokers and asthma was controlled by on demand short-acting β2-agonists only. Dose-response curves to M (0.15-80 μmol/mL) and NKA (3.4 (10−3)-0.88 μmol/mL) were performed on two separate days, and airway response was measured by FEV1 until a ≥20% fall from baseline (PC20FEV1). Twenty-two subjects reached a PC20FEV1 on both occasions. The PC20FEV1 values of both agonists correlated significantly (Spearman's r=−0.721; p=0.0002), and the relationship was given by 10log(PC20FEV1(NKA))=−1.36+ (0.60×10log(PC20FEV1(M)). We have demonstrated a significant relationship between airway responsiveness to NKA and methacholine in asthma. This suggests that both agonists may share common final pathways in causing bronchoconstriction in patients with mild persistent asthma. Based on our data and previous studies in asthma, it can be hypothesized that this direct NKA-induced bronchoconstrictor response may be mediated by predominant stimulation of the tachykinin NK-2 receptors on airway smooth muscle cells.