Carvedilol functions as a nonselective-adrenergic receptor (AR)/ 1-AR antagonist that is used for treatment of hypertension and heart failure. Carvedilol has been shown to function as an inverse agonist, inhibiting G protein activation while stimulating-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3’,5’-cyclic monophosphatestimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with theβ2-AR antagonist ICI-118551, but not the 1-AR antagonist atenolol or the 1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical 2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubuledisrupting compound nocodazole. Furthermore, immunocytochemis-try experiments and measurements of apical CFTR expression by Western blot analysis of biotinylated membranes revealed a decrease in the level of CFTR protein in monolayers treated with carvedilol but no significant change in monolayers treated with epinephrine. These results demonstrate that carvedilol binding to apical 2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.
|Original language||English (US)|
|Journal||American Journal of Physiology - Lung Cellular and Molecular Physiology|
|State||Published - Jan 1 2016|
- Bias ligands
- Inverse agonists
- β-arrestin signaling