In:
American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 310, No. 1 ( 2016-01-01), p. L50-L58
Abstract:
Carvedilol functions as a nonselective β-adrenergic receptor (AR)/α 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 β-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current ( I sc ) measurements using human airway epithelial cells revealed that, unlike β-AR agonists, which increase I sc , carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate-stimulated current. The decrease in I sc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with the β 2 -AR antagonist ICI-118551, but not the β 1 -AR antagonist atenolol or the α 1 -AR antagonist prazosin, indicating that its inhibitory effect on I sc was mediated through interactions with apical β 2 -ARs. However, the carvedilol effect was blocked by pretreatment with the microtubule-disrupting compound nocodazole. Furthermore, immunocytochemistry 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 β 2 -ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.
Type of Medium:
Online Resource
ISSN:
1040-0605
,
1522-1504
DOI:
10.1152/ajplung.00296.2015
Language:
English
Publisher:
American Physiological Society
Publication Date:
2016
detail.hit.zdb_id:
1477300-4
SSG:
12
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