Effect of cyclic AMP-elevating agents on airway ciliary beat frequency in central and lateral airways in rat precision-cut lung slices

In patients with chronic obstructive pulmonary disease (COPD), mucociliary clearance of the respiratory tract is impaired due to enhanced mucus secretion and deterioration of normal ciliary activity. We investigated the effects of cyclic AMP-elevating agents with a different mode of action on ciliary beat frequency (CBF) in rat large central and small lateral airways by comparing the phosphodiesterase-4 (PDE4) inhibitors rolipram and roflumilast to the β2-adrenoceptor agonist terbutaline and the adenylyl cyclase activator forskolin. Rat precision-cut lung slices were prepared and effects of cyclic AMP-elevating agents on CBF were assessed for up to 4 h. In central airways a time- and concentration-dependent increase in CBF was seen for roflumilast (59 ± 4%, 1 µM, 60 min), rolipram (55 ± 4%, 1 µM, 60 min), terbutaline (64 ± 8%, 10 µM, 60 min) and forskolin (55 ± 8%, 100 µM, 60 min). Only roflumilast and rolipram increased CBF in lateral airways, with a similar time course and maximum efficacy (roflumilast 48 ± 5%, rolipram 54 ± 2%). Incubation of lateral airways with terbutaline (10 µM, + 11%) or forskolin (100 µM, + 1%) had negligible effects. As a major novel finding this study reveals that PDE4 inhibitors increased CBF in central as well as in lateral airways, while terbutaline and forskolin affected CBF in proximal airways only.