We have previously demonstrated that intravenous and inhaled atrial natriuretic peptide (ANP) significantly inhibits histamine induced bronchoconstriction in asthmatic patients. The current study was designed to determine whether inhaled ANP was also able to inhibit the effects of methacholine. Eight atopic asthmatic patients (five women) were studied: mean (SD) age 38.2 (8.3) years flow expiratory volume per second (FEV1) 2.97 (0.60) litres, equivalent to 92 (13) % of the predicted. Each had demonstrated at least mild bronchial hyperreactivity to inhaled methacholine at screening (geometric mean PC20 1.02 mg/ml; range 0.11-6.54 mg/ml). Patients attended for 3 study days and after baseline spirometry received 3.5 ml saline (placebo), 0.1 mg ANP or 1 mg ANP (ANP dissolved in 3.5 ml saline) in a randomized, double-blind manner via a Mizer aerosol conservation device. Aerosolization took approximately 9 min and FEV1 was repeated at 0.5, 1.5 and 3 min after completion. Immediately thereafter each patient received a 2 min inhalation of methacholine at a dose individually calculated to give a 25% fall in FEV1 (as extrapolated at their initial screening visit) and the FEV1 was followed over the next 20 min. Mean (SEM)% FEV1 did not change significantly after ANP being -4.3 (1.7), -3.2 (2.7) and -2.4 (1.2) after placebo, 0.1 mg ANP and 1 mg ANP respectively. The mean (SEM) maximum fall in FEV1 after methacholine was as follows: placebo 26.9 (5.7)%, 0.1 mg ANP 18.2 (4.3)% and 1.0 mg 11.2 (2.7)% (P < 0.05 placebo vs 1 mg ANP). These results demonstrate that ANP offers significant protection against methacholine induced bronchoconstriction in asthmatic patients.