Tracheas from control rats or rats sensitized to egg albumin (EA) were studied in vitro in Ussing chambers, and changes in short-circuit current (Isc) induced by the addition of antigen or agonists on the mucosal (luminal) side were recorded. Addition of EA (100 micrograms/ml) to tracheas from sensitized but not from control rats caused a slow increase of Isc beginning after 15 to 30 s and maximal at 3 to 4 min. This response was inhibited in the presence of doxantrazole, a mucosal mast-cell-stabilizing agent, but not by sodium cromoglycate. A separate group of rats was treated neonatally with capsaicin to deplete peptide neurotransmitters. Responses to EA were significantly lower in capsaicin-treated, sensitized rats than in untreated, sensitized control littermates. No difference was seen in the level of serum EA-specific IgE in these two groups. In tracheas from untreated rats, addition of substance P, capsaicin, platelet-activating factor, and acetylcholine caused an immediate and marked increase in Isc. Responses to substance P and acetylcholine were unaffected by capsaicin treatment. However, responses to capsaicin itself and also to PAF were reduced. These data indicate that changes of net ion transport across the airway epithelium are early phenomena of local hypersensitivity reactions, and that neurotransmitters such as substance P may play an important role in the control of these phenomena.