Endogenous Hydrogen Sulfide Contributes to Tone Generation in Porcine Lower Esophageal Sphincter Via Na
| Autor: | Xiaopeng, Bai, Eikichi, Ihara, Katsuya, Hirano, Yoshimasa, Tanaka, Kayoko, Nakano, Satomi, Kita, Takahiro, Iwamoto, Haruei, Ogino, Mayumi, Hirano, Yoshinao, Oda, Kazuhiko, Nakamura, Yoshihiro, Ogawa |
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| Rok vydání: | 2017 |
| Předmět: |
PAG
propargylglycine CCh carbachol KES K+ extracellular solution L-Asp L-aspartic acid AOA amino-oxyacetic acid KATP channels ATP-sensitive K+ channels CBS cystathionine-β-synthase TEA tetraethylammonium H2S hydrogen sulfide NCX Na+/Ca2+ exchanger TG transgenic otorhinolaryngologic diseases Lower Esophageal Sphincter TTX tetrodotoxin 3MST 3-mercaptopyruvate sulfurtransferase Original Research [Ca2+]i cytosolic Ca2+ concentration L-NAME Nω-nitro-L-arginine methyl ester [Na+]o extracellular Na+ concentration Myogenic Tone Regulation NES normal extracellular solution CSE cystathionine-γ-lyase Hydrogen Sulfate ES extracellular solution LES lower esophageal sphincter L-Cys L-cysteine Na+/Ca2+ Exchanger |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| Popis: | Background and Aims Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question. Methods Isometric contraction was monitored in circular smooth muscle strips of porcine LES. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored in fura-2-loaded strips with front-surface fluorometry. The contribution of endogenous H2S to LES contractility was investigated by examining the effects of inhibitors of H2S-generating enzymes, including cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, on the LES function. Results Porcine LES strips myogenically maintained a tetrodotoxin-resistant basal tone. Application of AOA (cystathionine-β-synthase inhibitor) or L-aspartic acid (L-Asp; 3-mercaptopyruvate sulfurtransferase inhibitor) but not DL-PAG (cystathionine-γ-lyase inhibitor), decreased this basal tone. The relaxant effects of AOA and L-Asp were additive. Maximum relaxation was obtained by combination of 1 mM AOA and 3 mM L-Asp. Immunohistochemical analyses revealed that cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase, but not cystathionine-γ-lyase, were expressed in porcine LES. AOA+L-Asp–induced relaxation was accompanied by a decrease in [Ca2+]i and inversely correlated with the extracellular Na+ concentration ([Na+]o) (25-137.4 mM), indicating involvement of an Na+/Ca2+ exchanger. The reduction in the basal [Ca2+]i level by AOA was significantly augmented in the antral smooth muscle sheets of Na+/Ca2+ exchanger transgenic mice compared with wild-type mice. Conclusions Endogenous H2S regulates the LES myogenic tone by maintaining the basal [Ca2+]i via Na+/Ca2+ exchanger. H2S-generating enzymes may be a potential therapeutic target for esophageal motility disorders, such as achalasia. Graphical abstract |
| Databáze: | OpenAIRE |
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