| Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation. | |
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MedLine Citation:
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PMID: 15155267 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The widespread presence of the Na-K-2Cl (NKCC) cotransporter protein suggests that chronic administration of inhibitors may result in adverse effects. Inhibition of the NKCC cotransporter by loop diuretics is felt to underlie the diuretic and the pulmonary smooth muscle relaxant effects of this drug class. However, the fundamental regulation of salt and water movement by this cotransporter suggests that it may also mediate cell volume changes occurring during cell cycle progression. Thus we hypothesized that NKCC cotransporter inhibition by loop diuretics would decrease cellular proliferation. Normal human bronchial smooth muscle cells (BSMC) showed a significant concentration-dependent decrease in cell counts after 7 days of exposure to both bumetanide (n=5-10) and furosemide (n=6-16) compared with controls. Proliferation was similarly inhibited in normal human lung fibroblasts (n=5-9). To determine whether this was due to loss of cells, we performed apoptosis assays on BSMC. Both annexin V-propidium iodide staining (n=5-10) and single cell gel electrophoresis assays (n=4) were negative for necrosis and apoptosis in BSMC exposed to 10 microM bumetanide. Subsequent analysis of the cell cycle by flow cytometry showed that bumetanide-exposed BSMC were delayed in G1 phase compared with controls (n=4-8). This is the first evidence for loop diuretic inhibition of airway smooth muscle cell proliferation. NKCC cotransporter inhibition impeded G1-S phase transition without facilitating cell death. Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation. |
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Authors:
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Lynn M Iwamoto; Naomi Fujiwara; Kenneth T Nakamura; Randal K Wada |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2004-05-21 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 287 ISSN: 1040-0605 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2004 Sep |
Date Detail:
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Created Date: 2004-08-13 Completed Date: 2004-09-29 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L510-4 Citation Subset: IM |
Affiliation:
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Dept. of Pediatrics, Honolulu, HI 96826, USA. lynni@kapiolani.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects Biological Transport / drug effects, physiology Bronchi / cytology* Bumetanide / pharmacology Cell Count Cell Division / physiology Cell Survival / drug effects Cells, Cultured Diuretics / pharmacology Fibroblasts / cytology*, drug effects, metabolism* Furosemide / pharmacology G1 Phase / drug effects Humans Myocytes, Smooth Muscle / cytology*, drug effects, metabolism* S Phase / drug effects Sodium-Potassium-Chloride Symporters / antagonists & inhibitors, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P20 RR-11091/RR/NCRR NIH HHS; U54 RR-14607/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Diuretics; 0/Sodium-Potassium-Chloride Symporters; 0/sodium-potassium-chloride cotransporter 1 protein; 28395-03-1/Bumetanide; 54-31-9/Furosemide |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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