title: Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.
abstract: In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.
authors: Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany;
authors: Alisa M
authors: AM
authors: Agné
authors: Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany;
authors: Jan-Peter
authors: JP
authors: Baldin
authors: Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Audra R
authors: AR
authors: Benjamin
authors: Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Maria C
authors: MC
authors: Orogo-Wenn
authors: Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany;
authors: Lukas
authors: L
authors: Wichmann
authors: Department of Physiology, Indiana University School of Medicine-South Bend, South Bend, Indiana; and.
authors: Kenneth R
authors: KR
authors: Olson
authors: Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Dafydd V
authors: DV
authors: Walters
authors: Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany; mike.althaus@bio.uni-giessen.de.
authors: Mike
authors: M
authors: Althaus
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D065589:Respiratory Tract Absorption / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D013466:Sulfurtransferases / Q000235:genetics / Q000378:metabolism; D013726:Terbutaline / Q000494:pharmacology*; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D000318:Adrenergic beta-Agonists; D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D013440:Sulfides; D012964:Sodium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D013726:Terbutaline; C033479:sodium sulfide; D006862:Hydrogen Sulfide
keywords: ENaC; H2S; gasotransmitter; hydrogen sulfide; lung liquid clearance
references: FASEB J. 2002 Nov;16(13):1792-8
references: 12409322
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22090-5
references: 20007376
references: Antioxid Redox Signal. 2012 Jul 1;17(1):1-10
references: 22369066
references: Am J Physiol Lung Cell Mol Physiol. 2004 Aug;287(2):L411-9
references: 15090368
references: Br J Pharmacol. 2008 Dec;155(7):984-94
references: 18846041
references: PLoS One. 2014;9(3):e90965
references: 24603989
references: Biochem Biophys Res Commun. 2000 Jan 7;267(1):129-33
references: 10623586
references: Toxicol Lett. 2014 Jan 30;224(3):387-94
references: 24269241
references: J Physiol. 1974 Sep;241(2):327-57
references: 4443921
references: Eur J Pharmacol. 2014 Jun 5;732:32-42
references: 24657276
references: Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R297-312
references: 21543637
references: Front Physiol. 2012 Apr 18;3:101
references: 22529818
references: Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L843-51
references: 15208094
references: Cell Physiol Biochem. 2010;25(1):123-34
references: 20054151
references: Curr Mol Pharmacol. 2013 Mar;6(1):3-12
references: 23547930
references: Am J Respir Cell Mol Biol. 2001 Nov;25(5):554-61
references: 11713096
references: PLoS One. 2014;9(6):e100971
references: 24960042
references: Pflugers Arch. 2011 Aug;462(2):267-79
references: 21559843
references: Biol Pharm Bull. 2011;34(6):789-93
references: 21628873
references: Pediatr Res. 1991 Apr;29(4 Pt 1):357-61
references: 1852529
references: Nat Med. 2004 May;10(5):487-93
references: 15077107
references: Am J Physiol Regul Integr Comp Physiol. 2010 Jan;298(1):R51-60
references: 19889863
references: Br J Pharmacol. 2009 Nov;158(6):1442-53
references: 19845680
references: Physiol Rev. 2012 Apr;92(2):791-896
references: 22535897
references: Nature. 1994 Feb 3;367(6462):463-7
references: 8107805
references: Am J Physiol Lung Cell Mol Physiol. 2012 Jan 1;302(1):L133-9
references: 21949158
references: Acta Physiol Scand. 1958 Jun 2;42(3-4):298-308
references: 13544986
references: Am J Physiol Lung Cell Mol Physiol. 2014 Apr 1;306(7):L684-97
references: 24508731
references: Antioxid Redox Signal. 2014 Nov 20;21(15):2061-82
references: 24684506
references: Br J Pharmacol. 2011 Jan;162(2):392-404
references: 20840536
references: Respir Physiol. 1999 Jun 1;116(1):1-8
references: 10421029
references: Am J Respir Cell Mol Biol. 1997 Oct;17(4):508-18
references: 9376126
references: PLoS One. 2012;7(9):e46593
references: 23029554
references: Respir Physiol Neurobiol. 2007 Aug 15;158(1):97-106
references: 17490919
references: Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R243-52
references: 15345473
references: Physiol Rep. 2014 Jan 16;2(1):e00201
references: 24744880
references: Br J Pharmacol. 2012 Jul;166(6):1946-63
references: 22352810
references: Nat Genet. 1996 Mar;12(3):325-8
references: 8589728
references: J Physiol. 1986 Jul;376:321-40
references: 3795077
references: J Biol Chem. 2006 Feb 24;281(8):5158-68
references: 16373340
references: Annu Rev Physiol. 2004;66:77-101
references: 14977397
references: Annu Rev Pharmacol Toxicol. 1992;32:109-34
references: 1605565
references: Am J Respir Crit Care Med. 2001 May;163(6):1376-83
references: 11371404
references: Physiol Rev. 1997 Apr;77(2):359-96
references: 9114818
references: PLoS One. 2014;9(1):e87293
references: 24475266
references: Br J Pharmacol. 2012 Sep;167(2):368-82
references: 22509822
references: Front Physiol. 2012 Apr 09;3:83
references: 22509167
references: Respir Res. 2005;6:17
references: 15707485
references: Respir Physiol Neurobiol. 2004 Jan 15;139(2):133-44
references: 15122997
references: Nitric Oxide. 2014 Sep 15;41:11-26
references: 24928561
references: FASEB J. 2007 Oct;21(12):3329-37
references: 17536040
references: Anal Biochem. 2012 Feb 1;421(1):203-7
references: 22056407
references: J Appl Physiol (1985). 2012 Feb;112(3):411-8
references: 22074719
references: Am J Physiol Regul Integr Comp Physiol. 2008 Jun;294(6):R1930-7
references: 18417642
references: Exp Physiol. 2013 Feb;98(2):576-84
references: 22872661
references: Am J Respir Cell Mol Biol. 2009 May;40(5):588-600
references: 18952569
references: Anesthesiology. 2011 Nov;115(5):1012-21
references: 21912243
references: Med Gas Res. 2012 Oct 01;2(1):26
references: 23025523
references: Anesthesiology. 2010 Jul;113(1):104-15
references: 20574227
references: PLoS One. 2014;9(2):e88508
references: 24523906
references: Am J Physiol Lung Cell Mol Physiol. 2007 Nov;293(5):L1332-8
references: 17873005
references: Br J Pharmacol. 2009 Nov;158(5):1263-75
references: 19785650
references: J Physiol. 1983 Nov;344:137-52
references: 6655575
references: J Physiol. 1992 Mar;448:579-97
references: 1593479
references: Pediatr Res. 1978 Mar;12(3):239-42
references: 205826
references: Curr Mol Pharmacol. 2013 Mar;6(1):50-64
references: 23547935
references: N Engl J Med. 1999 Jul 15;341(3):156-62
references: 10403853
references: Anesthesiology. 2010 Jul;113(1):4-6
references: 20574223
references: Front Physiol. 2013 Jan 25;4:2
references: 23355823
references: Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R92-100
references: 20410470
references: Br J Clin Pharmacol. 2010 Jun;69(6):626-36
references: 20565454
references: Am J Respir Cell Mol Biol. 2011 Jan;44(1):53-65
references: 20139350
references: PLoS One. 2010;5(11):e15420
references: 21079763
references: Pflugers Arch. 1990 Apr;416(1-2):62-7
references: 2162035
references: Biochem J. 1982 Aug 15;206(2):267-77
references: 7150244
references: Antioxid Redox Signal. 2014 Jan 1;20(1):31-41
references: 23682813
references: Clin Chem Lab Med. 2013 Mar 1;51(3):623-32
references: 23196804
references: Platelets. 2014;25(3):166-74
references: 23586391
references: J Biomed Biotechnol. 2011;2011:174306
references: 22131798
references: Br J Pharmacol. 2013 Apr;168(8):1902-10
references: 23215842
references: J Appl Physiol (1985). 1990 May;68(5):2054-9
references: 2163379
references: Antioxid Redox Signal. 2013 Aug 10;19(5):448-64
references: 23199280
references: Pulm Med. 2011;2011:830320
references: 21637371
references: Pediatr Res. 2013 Apr;73(4 Pt 1):443-9
references: 23269118
references: Hum Mutat. 2009 Jul;30(7):1093-103
references: 19462466
references: J Dev Physiol. 1992 Feb;17(2):99-107
references: 1500638
references: Science. 2011 Nov 18;334(6058):986-90
references: 22096201
references: J Biomed Biotechnol. 2011;2011:978196
references: 22028593
references: J Clin Invest. 1987 Feb;79(2):335-43
references: 2879851