The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis

Authors

  • Stefano Fiorucci,

    Corresponding author
    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
    • University of Perugia, Gastroenterologia, Policlinico Monteluce, Via E. Dal Pozzo, 06122 Perugia, Italy
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    • fax: (39) 0755783883

  • Elisabetta Antonelli,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Andrea Mencarelli,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Stefano Orlandi,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Barbara Renga,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Giovanni Rizzo,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Eleonora Distrutti,

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Vijay Shah,

    1. GI Research Unit, Mayo Clinic, Rochester, MN
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  • Antonio Morelli

    1. Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy
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  • Potential conflict of interest: Nothing to report.

Abstract

The regulation of sinusoidal resistance is dependent on the contraction of hepatic stellate cells (HSC) around sinusoidal endothelial cell (SEC) through paracrine cross-talk of vasoconstrictor and vasodilator agents. Hydrogen sulfide (H2S), a recently discovered gas neurotransmitter, is a putative vasodilator whose role in hepatic vascular regulation and portal hypertension is unexplored. Four-week bile duct–ligated (BDL) rats with cirrhosis and control rats were treated daily with NaHS (56 μmol/kg) for 5 days. Isolated livers were perfused first with NaHS for 20 minutes and then with norepinephrine (NE) and the intrahepatic resistance studied. In normal rats and animals with cirrhosis, administration of NE resulted in a dose-dependent increase of portal pressure. This effect was attenuated by H2S treatment (P < .05). The H2S-induced relaxation of hepatic microcirculation was attenuated by glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel inhibitor. L-Cysteine, a substrate of cystathionine-gamma-lyase (CSE), decreased vasoconstriction in normal rat livers (P < .05) but failed to do so in livers with cirrhosis. BDL resulted in a downregulation of CSE mRNA/protein levels and activity (P < .05). Our in vitro data demonstrate that CSE is expressed in hepatocytes, HSCs, but not in sinusoidal endothelial cells (SEC). HSC activation downregulates CSE mRNA expression, resulting in a defective production of H2S and abrogation of relaxation induced by L-cysteine. In conclusion, CSE-derived H2S is involved in the maintenance of portal venous pressure. The reduction of CSE expression in the liver with cirrhosis contributes to the development of increased intrahepatic resistance and portal hypertension. (HEPATOLOGY 2005.)

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