Stimulation of airway mucociliary transport and epithelial ciliary motility by the triazolopyridazin derivative TAK-225.

To elucidate whether a newly developed antiallergic drug, the triazolopyridazin derivative TAK-225, alters airway mucociliary clearance and, if so, what the mechanism of action is, we measured mucociliary transport in the rabbit tracheal mucosa ex vivo and ciliary motility of the tracheal epithelium in vitro. Mucociliary transport function was determined by the transport rate of Evans blue dye that had been placed on the mucosal surface above the carina. Oral administration of TAK-225 (0.3-30 mg/kg) increased Evans blue transport toward the larynx in a dose-dependent manner. Addition of TAK-225 caused a rapid and sustained increase in the ciliary beat frequency of tracheal epithelium, as assessed by photoelectric method; the maximal increase from the base-line value was 25.1 +/- 4.6% (P < .01), and the concentration required to produce a half-maximal effect (EC50) was 3.1 +/- 0.8 x 10(-7) M. This effect was greatly attenuated by pretreatment with the cAMP antagonist adenosine 3',5'-cyclic monophosphorothioate, but not by Ca++-free medium containing ethylene glycol-bis [3-aminoethyl ether] N,N,N',N'-tetraacetic acid and [1,2-bis(2)aminophenoxy]ethane N,N,N',N'-tetraacetic acid-acetomethoxy ester. Incubation of tracheal epithelium with TAK-225 increased intracellular cAMP contents in a concentration-dependent manner. These results suggest that TAK-225 enhances airway mucociliary clearance probably through cAMP-mediated stimulation of ciliary motility of airway epithelium.