Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 308, Issue 7, Pages R636-R649Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00489.2014
Keywords
H2S; hydrogen sulfide; ENaC; lung liquid clearance; gasotransmitter
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Funding
- German Research Foundation (DFG) [AL1453/1-2]
- Dewey Bequest
- [NSF IOS 1051627]
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [1446310] Funding Source: National Science Foundation
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [1051627] Funding Source: National Science Foundation
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In pulmonary epithelia, beta-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 beta-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 mu M) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the beta-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. beta-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 mu M). 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-beta-synthase, cystathionine-gamma-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 beta-adrenergic agonists on lung liquid clearance.
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