Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl] in mouse airway cilia.

Carbocisteine (CCis), a mucoactive agent, is widely used to improve respiratory diseases. This study demonstrated that CCis increases ciliary bend angle (CBA) by 30% and ciliary beat frequency (CBF) by 10% in mouse airway ciliary cells. These increases were induced by an elevation in intracellular pH (pH; the pH pathway) and a decrease in the intracellular Cl concentration ([Cl]; the Cl pathway) stimulated by CCis. The Cl pathway, which is independent of CO/HCO, increased CBA by 20%. This pathway activated Cl release via activation of Cl channels, leading to a decrease in [Cl], and was inhibited by Cl channel blockers (5-nitro-2-(3-phenylpropylamino) benzoic acid and CFTR(inh)-172). Under the CO/HCO-free condition, the CBA increase stimulated by CCis was mimicked by the Cl-free NO solution. The pH pathway, which depends on CO/HCO, increased CBF and CBA by 10%. This pathway activated HCO entry via Na/HCO cotransport (NBC), leading to a pH elevation, and was inhibited by 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid. The effects of CCis were not affected by a protein kinase A inhibitor (1 μM PKI-A) or Ca-free solution. Thus, CCis decreased [Cl] via activation of Cl channels including CFTR, increasing CBA by 20%, and elevated pH via NBC activation, increasing CBF and CBA by 10%.