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Respiratory Research
Published in: Respiratory Research 1/2010

Open Access 01-12-2010 | Research

K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport

Authors: Dong-Yun Han, Hong-Guang Nie, Xiu Gu, Ramesh C Nayak, Xue-Feng Su, Jian Fu, Yongchang Chang, Vijay Rao, Hong-Long Ji

Published in: Respiratory Research | Issue 1/2010

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Abstract

Background

Lung epithelial Na+ channels (ENaC) are regulated by cell Ca2+ signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K+ channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K+ channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC) by up-regulating both apical and basolateral ion transport.

Methods

Verapamil-induced depression of heterologously expressed human αβγ ENaC in Xenopus oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441), and in vivo alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca2+ signal in H441 cells was analyzed using Fluo 4AM.

Results

The rate of in vivo AFC was reduced significantly (40.6 ± 6.3% of control, P < 0.05, n = 12) in mice intratracheally administrated verapamil. KCa3.1 (1-EBIO) and KATP (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 Ca2+ signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca2+ in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, KV (pyrithione-Na), K Ca3.1 (1-EBIO), and KATP (minoxidil) channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na+ and K+ transport pathways.

Conclusions

Our observations demonstrate that K+ channel openers are capable of rescuing reduced vectorial Na+ transport across lung epithelial cells with impaired Ca2+ signal.
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Literature
1.
Sami Karti S, Ulusoy H, Yandi M, Gunduz A, Kosucu M, Erol K, Ratip S: Non-cardiogenic pulmonary oedema in the course of verapamil intoxication. Emerg Med J 2002,19(5):458–459.CrossRefPubMed
2.
Nassar AH, Ghazeeri G, Usta IM: Nifedipine-associated pulmonary complications in pregnancy. Int J Gynaecol Obstet 2007,97(2):148–149.CrossRefPubMed
3.
Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V, Provost-Helou N, Ducloy-Bouthors AS, Puech F, Subtil D: Acute pulmonary oedema during nicardipine therapy for premature labour; Report of five cases. Eur J Obstet Gynecol Reprod Biol 2004,113(1):98–99.CrossRefPubMed
4.
Abbas OM, Nassar AH, Kanj NA, Usta IM: Acute pulmonary edema during tocolytic therapy with nifedipine. Am J Obstet Gynecol 2006,195(4):e3–4.CrossRefPubMed
5.
Janower S, Carbonne B, Lejeune V, Apfelbaum D, Boccara F, Cohen A: Acute pulmonary edema during preterm labor: role of nicardipine tocolysis (three cases). J Gynecol Obstet Biol Reprod (Paris) 2005,34(8):807–812.CrossRef
6.
Chapuis C, Menthonnex E, Debaty G, Koch FX, Rancurel E, Menthonnex P, Pons JC: Acute pulmonary edema during nicardipine and salbutamol therapy for preterm labor in twin pregnancy. J Gynecol Obstet Biol Reprod (Paris) 2005,34(5):493–496.CrossRef
7.
Stanek EJ, Nelson CE, DeNofrio D: Amlodipine overdose. Ann Pharmacother 1997,31(7–8):853–856.PubMed
8.
Humbert VH Jr, Munn NJ, Hawkins RF: Noncardiogenic pulmonary edema complicating massive diltiazem overdose. Chest 1991,99(1):258–259.CrossRefPubMed
9.
Brass BJ, Winchester-Penny S, Lipper BL: Massive verapamil overdose complicated by noncardiogenic pulmonary edema. Am J Emerg Med 1996,14(5):459–461.CrossRefPubMed
10.
Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002, 82:569–600.CrossRefPubMed
11.
Eaton DC, Helms MN, Koval M, Bao HF, Jain L: The Contribution of Epithelial Sodium Channels to Alveolar Function in Health and Disease. Annu Rev Physiol 2009, 71:403–423.CrossRefPubMed
12.
Matalon S, Lazrak A, Jain L, Eaton DC: Invited review: biophysical properties of sodium channels in lung alveolar epithelial cells. J Appl Physiol 2002,93(5):1852–1859.CrossRefPubMed
13.
Zemans RL, Matthay MA: Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury. Crit Care 2004,8(6):469–477.CrossRefPubMedPubMedCentral
14.
Matthay MA, Robriquet L, Fang X: Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc 2005,2(3):206–213.CrossRefPubMed
15.
Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, Schmidt A, Boucher R, Rossier BC: Early death due to defective neonatal lung liquid clearance in α-ENaC-deficient mice. Nat Genet 1996,12(3):325–328.CrossRefPubMed
16.
Chen L, Song W, Davis IC, Shrestha K, Schwiebert E, Sullender WM, Matalon S: Inhibition of Na + transport in lung epithelial cells by respiratory syncytial virus infection. Am J Respir Cell Mol Biol 2009,40(5):588–600.CrossRefPubMed
17.
Rossier BC, Pradervand S, Schild L, Hummler E: Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 2002, 64:877–897.CrossRefPubMed
18.
O'Grady SM, Lee SY: Molecular diversity and function of voltage-gated (Kv) potassium channels in epithelial cells. Int J Biochem Cell Biol 2005,37(8):1578–1594.CrossRefPubMed
19.
Inglis SK, Brown SG, Constable MJ, McTavish N, Olver RE, Wilson SM: A Ba 2+ -resistant, acid-sensitive K + conductance in Na + -absorbing H441 human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2007,292(5):L1304–1312.CrossRefPubMedPubMedCentral
20.
O'Grady SM, Lee SY: Chloride and potassium channel function in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2003,284(5):L689–700.CrossRefPubMed
21.
Leroy C, Dagenais A, Berthiaume Y, Brochiero E: Molecular identity and function in transepithelial transport of K(ATP) channels in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2004,286(5):L1027–1037.CrossRefPubMed
22.
Bardou O, Trinh NT, Brochiero E: Molecular diversity and function of K + channels in airway and alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2008.
23.
Greenwood IA, Yeung SY, Hettiarachi S, Andersson M, Baines DL: KCNQ-encoded channels regulate Na + transport across H441 lung epithelial cells. Pflugers Arch 2009,457(4):785–794.CrossRefPubMed
24.
Bernard K, Bogliolo S, Soriani O, Ehrenfeld J: Modulation of calcium-dependent chloride secretion by basolateral SK4-like channels in a human bronchial cell line. J Membr Biol 2003,196(1):15–31.CrossRefPubMed
25.
Leroy C, Prive A, Bourret JC, Berthiaume Y, Ferraro P, Brochiero E: Regulation of ENaC and CFTR expression with K + channel modulators and effect on fluid absorption across alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2006,291(6):L1207–1219.CrossRefPubMed
26.
Szkotak AJ, Ng AM, Sawicka J, Baldwin SA, Man SF, Cass CE, Young JD, Duszyk M: Regulation of K + current in human airway epithelial cells by exogenous and autocrine adenosine. Am J Physiol Cell Physiol 2001,281(6):C1991–2002.PubMed
27.
Monaghan AS, Baines DL, Kemp PJ, Olver RE: Inwardly rectifying K + currents of alveolar type II cells isolated from fetal guinea-pig lung: regulation by G protein- and Mg 2+ -dependent pathways. Pflugers Arch 1997,433(3):294–303.CrossRefPubMed
28.
Berthiaume Y, Folkesson HG, Matthay MA: Lung edema clearance: 20 years of progress: invited review: alveolar edema fluid clearance in the injured lung. J Appl Physiol 2002,93(6):2207–2213.CrossRefPubMed
29.
Sakuma T, Takahashi K, Ohya N, Nakada T, Matthay MA: Effects of ATP-sensitive potassium channel opener on potassium transport and alveolar fluid clearance in the resected human lung. Pharmacol Toxicol 1998,83(1):16–22.CrossRefPubMed
30.
Peth S, Karle C, Dehnert C, Bartsch P, Mairbaurl H: K + channel activation with minoxidil stimulates nasal-epithelial ion transport and blunts exaggerated hypoxic pulmonary hypertension. High Alt Med Biol 2006,7(1):54–63.CrossRefPubMed
31.
Briot R, Frank JA, Uchida T, Lee JW, Calfee CS, Matthay MA: Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs. Chest 2009,135(2):269–275.CrossRefPubMed
32.
Factor P, Mutlu GM, Chen L, Mohameed J, Akhmedov AT, Meng FJ, Jilling T, Lewis ER, Johnson MD, Xu A, et al.: Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci USA 2007,104(10):4083–4088.CrossRefPubMedPubMedCentral
33.
Lazrak A, Nita I, Subramaniyam D, Wei S, Song W, Ji HL, Janciauskiene S, Matalon S: α1-antitrypsin inhibits epithelial Na + transport in vitro and in vivo . Am J Respir Cell Mol Biol 2009,41(3):261–270.CrossRefPubMedPubMedCentral
34.
Gu X, Wang Z, Xu J, Maeda S, Sugita M, Sagawa M, Toga H, Sakuma T: Denopamine stimulates alveolar fluid clearance via cystic fibrosis transmembrane conductance regulator in rat lungs. Respirology 2006,11(5):566–571.CrossRefPubMed
35.
Chen L, Patel RP, Teng X, Bosworth CA, Lancaster JR Jr, Matalon S: Mechanisms of cystic fibrosis transmembrane conductance regulator activation by S-nitrosoglutathione. J Biol Chem 2006,281(14):9190–9199.CrossRefPubMed
36.
Thome U, Chen L, Factor P, Dumasius V, Freeman B, Sznajder JI, Matalon S: Na, K-ATPase gene transfer mitigates an oxidant-induced decrease of active sodium transport in rat fetal ATII cells. Am J Respir Cell Mol Biol 2001,24(3):245–252.CrossRefPubMed
37.
Thome UH, Davis IC, Nguyen SV, Shelton BJ, Matalon S: Modulation of sodium transport in fetal alveolar epithelial cells by oxygen and corticosterone. Am J Physiol Lung Cell Mol Physiol 2003,284(2):L376–385.CrossRefPubMed
38.
Guo Y, DuVall MD, Crow JP, Matalon S: Nitric oxide inhibits Na + absorption across cultured alveolar type II monolayers. Am J Physiol 1998,274(3 Pt 1):L369–377.PubMed
39.
Kirk KL, Halm DR, Dawson DC: Active sodium transport by turtle colon via an electrogenic Na-K exchange pump. Nature 1980,287(5779):237–239.CrossRefPubMed
40.
Ji HL, Su XF, Kedar S, Li J, Barbry P, Smith PR, Matalon S, Benos DJ: δ-subunit confers novel biophysical features to αβγ-human epithelial sodium channel (ENaC) via a physical interaction. J Biol Chem 2006,281(12):8233–8241.CrossRefPubMed
41.
Musa-Aziz R, Oliveira-Souza M, Mello-Aires M: Signaling pathways in the biphasic effect of ANG II on Na + /H + exchanger in T84 cells. J Membr Biol 2005,205(2):49–60.CrossRefPubMed
42.
Espelt MV, Estevez AY, Yin X, Strange K: Oscillatory Ca 2+ signaling in the isolated Caenorhabditis elegans intestine: role of the inositol-1,4,5-trisphosphate receptor and phospholipases C β and γ. J Gen Physiol 2005,126(4):379–392.CrossRefPubMedPubMedCentral
43.
Pendurthi UR, Ngyuen M, Andrade-Gordon P, Petersen LC, Rao LV: Plasmin induces Cyr61 gene expression in fibroblasts via protease-activated receptor-1 and p44/42 mitogen-activated protein kinase-dependent signaling pathway. Arterioscler Thromb Vasc Biol 2002,22(9):1421–1426.CrossRefPubMed
44.
Praetorius HA, Leipziger J: Released nucleotides amplify the cilium-dependent, flow-induced [Ca 2+ ] i response in MDCK cells. Acta Physiol (Oxf) 2009,197(3):241–251.CrossRef
45.
Lazrak A, Matalon S: cAMP-induced changes of apical membrane potentials of confluent H441 monolayers. Am J Physiol Lung Cell Mol Physiol 2003,285(2):L443–450.CrossRefPubMed
46.
Thomas CP, Campbell JR, Wright PJ, Husted RF: cAMP-stimulated Na + transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1. Am J Physiol Lung Cell Mol Physiol 2004,287(4):L843–851.CrossRefPubMed
47.
Nie HG, Chen L, Han DY, Li J, Song WF, Wei SP, Fang XH, Gu X, Matalon S, Ji HL: Regulation of epithelial sodium channels by cGMP/PKGII. J Physiol 2009,587(Pt 11):2663–2676.CrossRefPubMedPubMedCentral
48.
Woollhead AM, Baines DL: Forskolin-induced cell shrinkage and apical translocation of functional enhanced green fluorescent protein-human αENaC in H441 lung epithelial cell monolayers. J Biol Chem 2006,281(8):5158–5168.CrossRefPubMed
49.
Zhang S, Zhou Z, Gong Q, Makielski JC, January CT: Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res 1999,84(9):989–998.CrossRefPubMed
50.
Gao Y, Chotoo CK, Balut CM, Sun F, Bailey MA, Devor DC: Role of S3 and S4 transmembrane domain charged amino acids in channel biogenesis and gating of KCa2.3 and KCa3.1. J Biol Chem 2008,283(14):9049–9059.CrossRefPubMedPubMedCentral
51.
Bancila V, Cens T, Monnier D, Chanson F, Faure C, Dunant Y, Bloc A: Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat KATP channel. J Biol Chem 2005,280(10):8793–8799.CrossRefPubMed
52.
Swaminath G, Lee TW, Kobilka B: Identification of an allosteric binding site for Zn 2+ on the β2 adrenergic receptor. J Biol Chem 2003,278(1):352–356.CrossRefPubMed
53.
Amuzescu B, Segal A, Flonta ML, Simaels J, Van Driessche W: Zinc is a voltage-dependent blocker of native and heterologously expressed epithelial Na + channels. Pflugers Arch 2003,446(1):69–77.CrossRefPubMed
54.
Bossy-Wetzel E, Talantova MV, Lee WD, Scholzke MN, Harrop A, Mathews E, Gotz T, Han J, Ellisman MH, Perkins GA, et al.: Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K + channels. Neuron 2004,41(3):351–365.CrossRefPubMed
55.
Norlin A, Folkesson HG: Ca 2+ -dependent stimulation of alveolar fluid clearance in near-term fetal guinea pigs. Am J Physiol Lung Cell Mol Physiol 2002,282(4):L642–649.CrossRefPubMed
56.
Swystun V, Chen L, Factor P, Siroky B, Bell PD, Matalon S: Apical trypsin increases ion transport and resistance by a phospholipase C-dependent rise of Ca 2+ . Am J Physiol Lung Cell Mol Physiol 2005,288(5):L820–830.CrossRefPubMed
57.
Marunaka Y, Niisato N: Effects of Ca 2+ channel blockers on amiloride-sensitive Na + permeable channels and Na + transport in fetal rat alveolar type II epithelium. Biochem Pharmacol 2002,63(8):1547–1552.CrossRefPubMed
58.
Niisato N, Nakahari T, Tanswell AK, Marunaka Y: β2-agonist regulation of cell volume in fetal distal lung epithelium by cAMP-independent Ca 2+ release from intracellular stores. Can J Physiol Pharmacol 1997,75(8):1030–1033.CrossRefPubMed
59.
Marunaka Y, Niisato N, O'Brodovich H, Eaton DC: Regulation of an amiloride-sensitive Na + -permeable channel by a β2-adrenergic agonist, cytosolic Ca 2+ and Cl - in fetal rat alveolar epithelium. J Physiol 1999,515(Pt 3):669–683.CrossRefPubMedPubMedCentral
60.
Ismailov II, Berdiev BK, Shlyonsky VG, Benos DJ: Mechanosensitivity of an epithelial Na + channel in planar lipid bilayers: release from Ca 2+ block. Biophys J 1997,72(3):1182–1192.CrossRefPubMedPubMedCentral
61.
Schild L, Schneeberger E, Gautschi I, Firsov D: Identification of amino acid residues in the α, β, and γ subunits of the epithelial sodium channel (ENaC) involved in amiloride block and ion permeation. J Gen Physiol 1997,109(1):15–26.CrossRefPubMedPubMedCentral
62.
Chen Y, Cai T, Yang C, Turner DA, Giovannucci DR, Xie Z: Regulation of inositol 1,4,5-trisphosphate receptor-mediated calcium release by the Na/K-ATPase in cultured renal epithelial cells. J Biol Chem 2008,283(2):1128–1136.CrossRefPubMed
63.
DeWitt CR, Waksman JC: Pharmacology, pathophysiology and management of calcium channel blocker and β-blocker toxicity. Toxicol Rev 2004,23(4):223–238.CrossRefPubMed
64.
Hohenhaus E, Niroomand F, Goerre S, Vock P, Oelz O, Bartsch P: Nifedipine does not prevent acute mountain sickness. Am J Respir Crit Care Med 1994,150(3):857–860.CrossRefPubMed
65.
Ninomiya T, Takano M, Haruna T, Kono Y, Horie M: Verapamil, a Ca 2+ entry blocker, targets the pore-forming subunit of cardiac type KATP channel (Kir6.2). J Cardiovasc Pharmacol 2003,42(2):161–168.CrossRefPubMed
66.
Pancrazio JJ, Viglione MP, Kleiman RJ, Kim YI: Verapamil-induced blockade of voltage-activated K + current in small-cell lung cancer cells. J Pharmacol Exp Ther 1991,257(1):184–191.PubMed
67.
Waldegger S, Niemeyer G, Morike K, Wagner CA, Suessbrich H, Busch AE, Lang F, Eichelbaum M: Effect of verapamil enantiomers and metabolites on cardiac K + channels expressed in Xenopus oocytes. Cell Physiol Biochem 1999,9(2):81–89.CrossRefPubMed
Metadata
Title
K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport
Authors
Dong-Yun Han
Hong-Guang Nie
Xiu Gu
Ramesh C Nayak
Xue-Feng Su
Jian Fu
Yongchang Chang
Vijay Rao
Hong-Long Ji
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2010
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-11-65

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