K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport
<p>Abstract</p> <p>Background</p> <p>Lung epithelial Na<sup>+ </sup>channels (ENaC) are regulated by cell Ca<sup>2+ </sup>signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K<sup>+ </sup>cha...
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doaj-d4f83a02e19a42099bf5adec3e4f24562020-11-25T01:17:54ZengBMCRespiratory Research1465-99212010-05-011116510.1186/1465-9921-11-65K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transportSu Xue-FengNayak Ramesh CGu XiuNie Hong-GuangHan Dong-YunFu JianChang YongchangRao VijayJi Hong-Long<p>Abstract</p> <p>Background</p> <p>Lung epithelial Na<sup>+ </sup>channels (ENaC) are regulated by cell Ca<sup>2+ </sup>signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K<sup>+ </sup>channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K<sup>+ </sup>channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC) by up-regulating both apical and basolateral ion transport.</p> <p>Methods</p> <p>Verapamil-induced depression of heterologously expressed human αβγ ENaC in <it>Xenopus </it>oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441), and <it>in vivo </it>alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca<sup>2+ </sup>signal in H441 cells was analyzed using Fluo 4AM.</p> <p>Results</p> <p>The rate of <it>in vivo </it>AFC was reduced significantly (40.6 ± 6.3% of control, <it>P </it>< 0.05, n = 12) in mice intratracheally administrated verapamil. K<sub>Ca3.1 </sub>(1-EBIO) and K<sub>ATP </sub>(minoxidil) channel openers significantly recovered AFC. In addition to short-circuit current (Isc) in intact H441 monolayers, both apical and basolateral Isc levels were reduced by verapamil in permeabilized monolayers. Moreover, verapamil significantly altered Ca<sup>2+ </sup>signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca<sup>2+ </sup>in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, K<sub>V </sub>(pyrithione-Na), K <sub>Ca3.1 </sub>(1-EBIO), and K<sub>ATP </sub>(minoxidil) channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na<sup>+ </sup>and K<sup>+ </sup>transport pathways.</p> <p>Conclusions</p> <p>Our observations demonstrate that K<sup>+ </sup>channel openers are capable of rescuing reduced vectorial Na<sup>+ </sup>transport across lung epithelial cells with impaired Ca<sup>2+ </sup>signal.</p> http://respiratory-research.com/content/11/1/65 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Su Xue-Feng Nayak Ramesh C Gu Xiu Nie Hong-Guang Han Dong-Yun Fu Jian Chang Yongchang Rao Vijay Ji Hong-Long |
spellingShingle |
Su Xue-Feng Nayak Ramesh C Gu Xiu Nie Hong-Guang Han Dong-Yun Fu Jian Chang Yongchang Rao Vijay Ji Hong-Long K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport Respiratory Research |
author_facet |
Su Xue-Feng Nayak Ramesh C Gu Xiu Nie Hong-Guang Han Dong-Yun Fu Jian Chang Yongchang Rao Vijay Ji Hong-Long |
author_sort |
Su Xue-Feng |
title |
K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
title_short |
K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
title_full |
K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
title_fullStr |
K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
title_full_unstemmed |
K<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
title_sort |
k<sup>+ </sup>channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport |
publisher |
BMC |
series |
Respiratory Research |
issn |
1465-9921 |
publishDate |
2010-05-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Lung epithelial Na<sup>+ </sup>channels (ENaC) are regulated by cell Ca<sup>2+ </sup>signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K<sup>+ </sup>channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K<sup>+ </sup>channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC) by up-regulating both apical and basolateral ion transport.</p> <p>Methods</p> <p>Verapamil-induced depression of heterologously expressed human αβγ ENaC in <it>Xenopus </it>oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441), and <it>in vivo </it>alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca<sup>2+ </sup>signal in H441 cells was analyzed using Fluo 4AM.</p> <p>Results</p> <p>The rate of <it>in vivo </it>AFC was reduced significantly (40.6 ± 6.3% of control, <it>P </it>< 0.05, n = 12) in mice intratracheally administrated verapamil. K<sub>Ca3.1 </sub>(1-EBIO) and K<sub>ATP </sub>(minoxidil) channel openers significantly recovered AFC. In addition to short-circuit current (Isc) in intact H441 monolayers, both apical and basolateral Isc levels were reduced by verapamil in permeabilized monolayers. Moreover, verapamil significantly altered Ca<sup>2+ </sup>signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca<sup>2+ </sup>in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, K<sub>V </sub>(pyrithione-Na), K <sub>Ca3.1 </sub>(1-EBIO), and K<sub>ATP </sub>(minoxidil) channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na<sup>+ </sup>and K<sup>+ </sup>transport pathways.</p> <p>Conclusions</p> <p>Our observations demonstrate that K<sup>+ </sup>channel openers are capable of rescuing reduced vectorial Na<sup>+ </sup>transport across lung epithelial cells with impaired Ca<sup>2+ </sup>signal.</p> |
url |
http://respiratory-research.com/content/11/1/65 |
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