Atrial natriuretic peptide (ANP) is secreted by cardiac atria and lung tissue; it has a bronchodilator action in normal subjects and patients with asthma and has been shown to protect against histamine-induced bronchoconstriction in patients with asthma. Bronchoconstriction caused by inhalation of ultrasonically nebulized distilled water (fog), in contrast to histamine-induced bronchoconstriction, has features in common with exercise-induced asthma but can be given more easily in a dose-response fashion. The present study aimed to determine the effect of elevated plasma ANP concentrations on the bronchoconstrictor response to inhalation of fog. Eight patients with atopic asthma were studied, mean baseline FEV₁ 3.001, equivalent to 89% (range 76–103%) predicted. The provocation dose of fog producing a 25% fall in FEV₁ (PD₂₅) was determined for each subject. On 4 study days, subjects received an intravenous infusion of placebo or ANP at a rate of 1.25, 3.0, or 10.0 pmol/kg/min in randomized, double-blind manner for 30 min to allow steady-state plasma concentrations to be achieved; the PD₂₅ fog was then administered and FEV₁ recorded over 30 min. Mean (SEM) baseline plasma ANP concentration was 19.3 (4.1) pg/ml and increased to 39.4 (6.6), 106.4 (11.1), and 445.9 (105.4) with the three rates of ANP infusion. The highest rate of infusion increased prechallenge FEV₁ by 8.7 (2.4)% (p < 0.01), but the lower rates of infusion had no effect. The mean (SEM) maximum percentage fall in FEV₁ following administration of the PD₂₅ fog during placebo infusion was 31.5 (5.3) and was 20.6 (5.1), 14.3 (4.2) (p < 0.05), and 10.9 (2.3) (p < 0.01) with respective ANP infusions. Area under the curve of percentage change in FEV₁ over 30 min was 564(123), 390(124), 190(81)(p < 0.05), and 177(42)(p < 0.01) for placebo and the three ANP infusions, respectively. These results indicate that elevated plasma ANP concentrations antagonize fog-induced bronchoconstriction; as a small increase in plasma, ANP concentration is seen in exercise, this may reduce the severity of exercise-induced bronchoconstriction in asthma. ANP may have a role as a local modulator of airway tone.