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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Main Authors: Su Xue-Feng, Nayak Ramesh C, Gu Xiu, Nie Hong-Guang, Han Dong-Yun, Fu Jian, Chang Yongchang, Rao Vijay, Ji Hong-Long
Format: Article
Language:English
Published: BMC 2010-05-01
Series:Respiratory Research
Online Access:http://respiratory-research.com/content/11/1/65
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spelling 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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