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  • Airway epithelial cells  (1)
  • Key words Triamterene  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Blockade of epithelial Na+ channels by triamterenes – underlying mechanisms and molecular basis (1996)
    Springer
    Pflügers Archiv 432 (1996), S. 760-766 
    Details
    ISSN: 1432-2013
    Keywords: Key words Triamterene ; Amiloride ; Na+ channel ; Epithelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The three subunits (α, β, γ) encoding for the rat epithelial Na+ channel (rENaC) were expressed in Xenopus oocytes, and the induced Na+ conductance was tested for its sensitivity to various triamterene derivatives. Triamterene blocked rENaC in a voltage-dependent manner, and was 100-fold less potent than amiloride at pH 7.5. At −90 mV and −40 mV, the IC50 values were 5 μM and 10 μM, respectively. The blockage by triamterene, which is a weak base with a pK a of 6.2, was dependent on the extracellular pH. The IC50 was 1 μM at pH 6.5 and only 17 μM at pH 8.5, suggesting that the protonated compound is more potent than the unprotonated one. According to a simple kinetic analysis, the apparent inhibition constants at −90 mV were 0.74 μM for the charged and 100.6 μM for the uncharged triamterene. The main metabolite of triamterene, p-hydroxytriamterene sulfuric acid ester, inhibited rENaC with an approximately twofold lower affinity. Derivatives of triamterene, in which the p-position of the phenylmoiety was substituted by acidic or basic residues, inhibited rENaC with IC50 values in the range of 0.1–20 μM. Acidic and basic triamterenes produced a rENaC blockade with a similar voltage and pH dependence as the parent compound, suggesting that the pteridinemoiety of triamterene is responsible for that characteristic. Expression of the rENaC α-subunit-deletion mutant, Δ278–283, which lacks a putative amiloride-binding site, induced a Na+ channel with a greatly reduced affinity for both triamterene and amiloride. In summary, rENaC is a molecular target for triamterene that binds to its binding site within the electrical field, preferably as a positively charged molecule in a voltage- and pH-dependent fashion. We propose that amiloride and triamterene bind to rENaC using very similar mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050196
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Culture-dependent expression of Na+ conductances in airway epithelial cells (1996)
    Springer
    Pflügers Archiv 431 (1996), S. 578-586 
    Details
    ISSN: 1432-2013
    Keywords: Key wordsαhENaC ; Airway epithelial cells ; Amiloride ; CFTR ; Patch clamp ; RT-PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract According to previous studies, amiloride-sensitive (Amil+) Na+ channels are present in apical membranes of airway epithelial cells. When isolated from intact tissue and grown in primary culture or as immortalized cell lines, these cells tend to lose these Amil+ Na+ channels. The present study examines this issue in immortalized human bronchial epithelial cells (16HBE14o-cell line). The mRNA of one subunit of the Na+ channel (αhENaC) was semi-quantified by polymerase chain reaction of reverse transcribed RNA. Transcripts were significantly increased when cells were exposed to aldosterone and dexamethasone irrespective of whether grown on permeable supports or plastic. When grown on plastic dishes 16HBE14o-cells showed cAMP-dependent Cl− currents in whole-cell (WC) patch-clamp experiments, corresponding to expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Na+ currents could not be detected although cells expressed significant amounts of αhENaC as demonstrated by Northern blot analysis. In contrast, when cells were grown on permeable supports or cultured in the presence of butyrate (5 mmol/l, plastic or permeable support) or aldo-sterone and dexamethasone (both 1 μmol/l, plastic or permeable support), amiloride (10 μmol/l) hyperpolarized the membrane voltage (ΔV m) by 2–9 mV, paralleled by small reductions of WC conductances (ΔG m) of 0.4–4.0 nS. The effects of amiloride on ΔVm were generally more pronounced (up to 12 mV) when cells were grown on permeable supports. The amiloride effect (ΔV m) was concentration dependent with an inhibitory constant, K i, of about 0.1 μmol/l. We further examined whether the induction of an Amil+ Na+ conductance was paralleled by additional changes in membrane conductance. In fact, the cAMP-activated Cl− conductance was significantly attenuated by approximately 80% (n = 35) in cells responding to amiloride, whilst the ATP-activated K+ conductance remained unaffected. The present data suggest that cellular mechanisms determining differentiation control the functional expression of Na+ and Cl− conductances in human airway epithelial cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240050038
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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