We investigated if healthy subjects could release NO upon hyperosmolar challenge as a defence mechanism, and whether asthmatics with atopy showed an altered response. A plot of NO output versus flow rate was used to calculate the alveolar level and the NO-flux from the airways. The asthmatics had a higher NO output and this was due to an increased NO-flux from the airways, 86+/-30 nl min(-1) compared with control 21+/-2 nl min(-1) (P<0.05). The alveolar NO levels showed no difference. In response to a dry powder of mannitol the exhaled NO concentration decreased in asthmatics by 37+/-7%, but increased in the control by 9+/-4% (P<0.001). The FEV(1.0) decreased 13+/-2% and airway conductance 42+/-7% in asthmatics and in the controls 2+/-1% and 0+/-7%, respectively (P<0.001). We conclude that asthmatics have an altered response to mannitol challenge in regards to exhaled NO. This may result from down regulation of constitutive NO production as a result of high levels of NO flux from the airways.