Document Detail

Pharmacological modulation of ion transport across wild-type and DeltaF508 CFTR-expressing human bronchial epithelia.
MedLine Citation:
PMID:  10913013     Owner:  NLM     Status:  MEDLINE    
Forskolin, UTP, 1-ethyl-2-benzimidazolinone (1-EBIO), NS004, 8-methoxypsoralen (Methoxsalen; 8-MOP), and genistein were evaluated for their effects on ion transport across primary cultures of human bronchial epithelium (HBE) expressing wild-type (wt HBE) and DeltaF508 (DeltaF-HBE) cystic fibrosis transmembrane conductance regulator. In wt HBE, the baseline short-circuit current (I(sc)) averaged 27.0 +/- 0.6 microA/cm(2) (n = 350). Amiloride reduced this I(sc) by 13.5 +/- 0.5 microA/cm(2) (n = 317). In DeltaF-HBE, baseline I(sc) was 33.8 +/- 1.2 microA/cm(2) (n = 200), and amiloride reduced this by 29.6 +/- 1.5 microA/cm(2) (n = 116), demonstrating the characteristic hyperabsorption of Na(+) associated with cystic fibrosis (CF). In wt HBE, subsequent to amiloride, forskolin induced a sustained, bumetanide-sensitive I(sc) (DeltaI(sc) = 8.4 +/- 0.8 microA/cm(2); n = 119). Addition of acetazolamide, 5-(N-ethyl-N-isopropyl)-amiloride, and serosal 4, 4'-dinitrostilben-2,2'-disulfonic acid further reduced I(sc), suggesting forskolin also stimulates HCO(3)(-) secretion. This was confirmed by ion substitution studies. The forskolin-induced I(sc) was inhibited by 293B, Ba(2+), clofilium, and quinine, whereas charybdotoxin was without effect. In DeltaF-HBE the forskolin I(sc) response was reduced to 1.2 +/- 0.3 microA/cm(2) (n = 30). In wt HBE, mucosal UTP induced a transient increase in I(sc) (Delta I(sc) = 15. 5 +/- 1.1 microA/cm(2); n = 44) followed by a sustained plateau, whereas in DeltaF-HBE the increase in I(sc) was reduced to 5.8 +/- 0. 7 microA/cm(2) (n = 13). In wt HBE, 1-EBIO, NS004, 8-MOP, and genistein increased I(sc) by 11.6 +/- 0.9 (n = 20), 10.8 +/- 1.7 (n = 18), 10.0 +/- 1.6 (n = 5), and 7.9 +/- 0.8 microA/cm(2) (n = 17), respectively. In DeltaF-HBE, 1-EBIO, NS004, and 8-MOP failed to stimulate Cl(-) secretion. However, addition of NS004 subsequent to forskolin induced a sustained Cl(-) secretory response (2.1 +/- 0.3 microA/cm(2), n = 21). In DeltaF-HBE, genistein alone stimulated Cl(-) secretion (2.5 +/- 0.5 microA/cm(2), n = 11). After incubation of DeltaF-HBE at 26 degrees C for 24 h, the responses to 1-EBIO, NS004, and genistein were all potentiated. 1-EBIO and genistein increased Na(+) absorption across DeltaF-HBE, whereas NS004 and 8-MOP had no effect. Finally, Ca(2+)-, but not cAMP-mediated agonists, stimulated K(+) secretion across both wt HBE and DeltaF-HBE in a glibenclamide-dependent fashion. Our results demonstrate that pharmacological agents directed at both basolateral K(+) and apical Cl(-) conductances directly modulate Cl(-) secretion across HBE, indicating they may be useful in ameliorating the ion transport defect associated with CF.
D C Devor; R J Bridges; J M Pilewski
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  279     ISSN:  0363-6143     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2000-08-24     Completed Date:  2000-08-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  C461-79     Citation Subset:  IM    
Department of Cell Biology and Physiology, University of Pittsburgh, Pennsylvania 15261, USA.
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MeSH Terms
Benzimidazoles / pharmacology
Bronchi / drug effects,  metabolism*
Cells, Cultured
Chloride Channels / drug effects,  metabolism*
Cystic Fibrosis / metabolism
Cystic Fibrosis Transmembrane Conductance Regulator / agonists,  genetics,  metabolism*
Dermatologic Agents / pharmacology
Enzyme Inhibitors / pharmacology
Epithelial Cells / drug effects,  metabolism*
Genistein / pharmacology
Ion Transport / drug effects,  physiology
Potassium Channels / drug effects,  metabolism*
Psoralens / pharmacology
Grant Support
Reg. No./Substance:
0/Benzimidazoles; 0/CFTR protein, human; 0/Chloride Channels; 0/Dermatologic Agents; 0/Enzyme Inhibitors; 0/Potassium Channels; 0/Psoralens; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 446-72-0/Genistein

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