J. Tamaoki et al., STIMULATION OF AIRWAY MUCOCILIARY TRANSPORT AND EPITHELIAL CILIARY MOTILITY BY THE TRIAZOLOPYRIDAZIN DERIVATIVE TAK-225, The Journal of pharmacology and experimental therapeutics, 281(3), 1997, pp. 1186-1190
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.