STIMULATION OF AIRWAY MUCOCILIARY TRANSPORT AND EPITHELIAL CILIARY MOTILITY BY THE TRIAZOLOPYRIDAZIN DERIVATIVE TAK-225

To elucidate whether a newly developed antiallergic drug, the triazolo pyridazin derivative TAK-225, alters airway mucociliary clearance and, if so, what, the mechanism of action is, we measured mucociliary tran sport in the rabbit tracheal mucosa ex vivo and ciliary motility of th e tracheal epithelium in vitro. Mucociliary transport function was det ermined by the transport rate of Evans blue dye that had been placed o n 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 sustaine d increase in the ciliary beat frequency of tracheal epithelium, as as sessed by photoelectric method; the maximal increase from the base-lin e 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 antagonis t adenosine 3',5'-cyclic monophosphorothioate, but not by Ca++-free me dium containing ethylene glycol-bis [beta-aminoethyl ether] N,N,N',N'- tetraacetic acid and [1,2-bis(2)aminophenoxy]ethane N,N,N',N'-tetraace tic acid-acetomethoxy eater. Incubation of tracheal epithelium with TA K-225 increased intracellular cAMP contents in a concentration-depende nt manner. These results suggest that TAK-225 enhances airway mucocili ary clearance probably through cAMP-mediated stimulation of ciliary mo tility of airway epithelium.