EFFECTS OF INHALED SUBSTANCE-P ON AIRWAY RESPONSIVENESS TO METHACHOLINE IN ASTHMATIC SUBJECTS IN-VIVO

We tested the hypothesis that the inhaled tachykinin substance P (SP) can induce hyperresponsiveness to methacholine in asthmatic subjects in vivo. Nine atopic nonsmoking asthmatic males with normal forced expiratory volume in 1 s (FEV(1); > 80% predicted) and increased methacholine sensitivity [provocative concn causing 20% fall in FEV(1) (PC20) < 8 mg/ml] participated in a two-period placebo-controlled crossover study. Dose-response curves to SP (0.25-8 mg/ml) and placebo were recorded on 2 randomized days at least 1 wk apart, and methacholine tests were done 24 h before and 2 and 24 h after these challenges. The responses were measured by FEV(1) (% fall from baseline). The position of the methacholine dose-response curves was expressed by the PC20 FEV(1) and by the maximal response by the plateau level (MFEV(1)). SP caused a dose-dependent fall in FEV(1) (P < 0.001). There was a slight increase in the PC20 FEV(1) at 2 and 24 h, which was not significantly different between placebo and SP. Similarly, there was a reduction in MFEV(1) at 2 h after both pretreatments. However, at 24 h after SP inhalation, MFEV(1) increased compared with placebo. These changes in MFEV(1) were significantly different between SP and placebo by 5.2 +/- 2.2% fall (SE) (P < 0.05). We conclude that 1) a bronchoconstrictive dose of SP, compared with placebo, enhances maximal airway narrowing to methacholine in asthma 24 h after inhalation and 2) tolerance develops to high doses of inhaled methacholine. These findings are suggestive of a role of SP in causing excessive airway narrowing in asthma by inflammatory mechanisms.