Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

Alisa M. Agné, Jan Peter Baldin, Audra R. Benjamin, Maria C. Orogo-Wenn, Lukas Wichmann, Kenneth Olson, Dafydd V. Walters, Mike Althaus

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

In pulmonary epithelia,_-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 agonistregulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50μM) 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 (5-50μM). 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.

Original languageEnglish (US)
Pages (from-to)R636-R649
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume308
Issue number7
DOIs
StatePublished - Apr 1 2015

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Adrenergic Agonists
Hydrogen Sulfide
Sodium
Lung
Amiloride
Cystathionine
Terbutaline
Epithelium
Epithelial Sodium Channels
1-Methyl-3-isobutylxanthine
Lyases
Xenopus laevis
Colforsin
Adrenergic Agents
Electrolytes
sodium sulfide
Adenosine Triphosphate
Epithelial Cells
Cell Membrane
Parturition

Keywords

  • ENaC
  • Gasotransmitter
  • H2S
  • Hydrogen sulfide
  • Lung liquid clearance

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption. / Agné, Alisa M.; Baldin, Jan Peter; Benjamin, Audra R.; Orogo-Wenn, Maria C.; Wichmann, Lukas; Olson, Kenneth; Walters, Dafydd V.; Althaus, Mike.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 308, No. 7, 01.04.2015, p. R636-R649.

Research output: Contribution to journalArticle

Agné, Alisa M. ; Baldin, Jan Peter ; Benjamin, Audra R. ; Orogo-Wenn, Maria C. ; Wichmann, Lukas ; Olson, Kenneth ; Walters, Dafydd V. ; Althaus, Mike. / Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2015 ; Vol. 308, No. 7. pp. R636-R649.
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AU - Baldin, Jan Peter

AU - Benjamin, Audra R.

AU - Orogo-Wenn, Maria C.

AU - Wichmann, Lukas

AU - Olson, Kenneth

AU - Walters, Dafydd V.

AU - Althaus, Mike

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N2 - In pulmonary epithelia,_-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 agonistregulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50μM) 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 (5-50μM). 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.

AB - In pulmonary epithelia,_-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 agonistregulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50μM) 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 (5-50μM). 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.

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