Adenosine A3 receptor-mediated potentiation of mucociliary transport and epithelial ciliary motility

To examine the effect of adenosine A(3) receptor stimulation on airway mucociliary clearance, we measured transport of Evans blue dye in rabbit trachea in vivo and ciliary motility of epithelium by the photoelectric method in vitro. Mucociliary transport was enhanced dose dependently by the selective A(3) agonist N-6-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) and to a lesser extent by the less-selective N-6-2-(4-amino-3-iodophenyl)ethyladenosine, whereas the A(1) agonist N-cyclopentyladenosine (CPA) and the A(2) agonist CGS-21680 had no effect. The effect of IB-MECA was abolished by pretreatment with the selective A(3) antagonist MRS-1220 but not by the A(1) antagonist 1,3-dipropyly-8-cyclopentylxanthine or the A(2) antagonist 3,7-dimethyl-L-propargylxanthine. Epithelial ciliary beat frequency was increased by IB-MECA in a concentration-dependent manner, the maximal increase being 33%, and this effect was inhibited by MRS-1220. The IB-MECA-induced ciliary stimulation was not altered by the Rp diastereomer of cAMP but was greatly inhibited by Ca2+-free medium containing BAPTA-AM. Incubation with IB-MECA increased intracellular Ca2+ contents. Therefore, A(3) agonist enhances airway mucociliary clearance probably through Ca2+-mediated stimulation of ciliary motility of airway epithelium.