The methionine connection: Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats

Eleonora Distrutti, Andrea Mencarelli, Luca Santucci, Barbara Renga, Stefano Orlandi, Annibale Donini, Vijay Shah, Stefano Fiorucci

Research output: Contribution to journalArticle

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Abstract

Increased intrahepatic resistance in cirrhotic livers is caused by endothelial dysfunction and impaired formation of two gaseous vasodilators, nitric oxide (NO) and hydrogen sulfide (H2S). Homocysteine, a sulfur-containing amino acid and H2S precursor, is formed from hepatic methionine metabolism. In the systemic circulation, hyperhomocystenemia impairs vasodilation and NO production from endothelial cells. Increased blood levels of homocysteine are common in patients with liver cirrhosis. In this study, we demonstrate that acute liver perfusion with homocysteine impairs NO formation and intrahepatic vascular relaxation induced by acetylcholine in methoxamine-precontracted normal livers (7.3% ± 3.0% versus 26% ± 2.7%; P < 0.0001). In rats with mild, diet-induced hyperhomocystenemia, the vasodilating activity of acetylcholine was markedly attenuated, and incremental increases in flow induced a greater percentage of increases in perfusion pressure than in control livers. Compared with normal rats, animals rendered cirrhotic by 12 weeks' administration of carbon tetrachloride exhibited a greater percentage of increments in perfusion pressure in response to shear stress (P < 0.05), and intrahepatic resistance to incremental increases in flow was further enhanced by homocysteine (P < 0.05). In normal hyperhomocysteinemic and cirrhotic rat livers, endothelial dysfunction caused by homocysteine was reversed by perfusion of the livers with sodium sulfide. Homocysteine reduced NO release from sinusoidal endothelial cells and also caused hepatic stellate cell contraction; this suggests a dual mechanism of action, with the latter effect being counteracted by H2S. Conclusion: Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalHepatology
Volume47
Issue number2
DOIs
StatePublished - Feb 2008

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Hydrogen Sulfide
Homocysteine
Microcirculation
Methionine
Liver
Nitric Oxide
Perfusion
Hepatic Stellate Cells
Vasodilation
Acetylcholine
Endothelial Cells
Methoxamine
Sulfur Amino Acids
Pressure
Carbon Tetrachloride
Portal Hypertension
Vasodilator Agents
Liver Cirrhosis
Blood Vessels
Liver Diseases

ASJC Scopus subject areas

  • Hepatology

Cite this

Distrutti, E., Mencarelli, A., Santucci, L., Renga, B., Orlandi, S., Donini, A., ... Fiorucci, S. (2008). The methionine connection: Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. Hepatology, 47(2), 659-667. https://doi.org/10.1002/hep.22037

The methionine connection : Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. / Distrutti, Eleonora; Mencarelli, Andrea; Santucci, Luca; Renga, Barbara; Orlandi, Stefano; Donini, Annibale; Shah, Vijay; Fiorucci, Stefano.

In: Hepatology, Vol. 47, No. 2, 02.2008, p. 659-667.

Research output: Contribution to journalArticle

Distrutti, E, Mencarelli, A, Santucci, L, Renga, B, Orlandi, S, Donini, A, Shah, V & Fiorucci, S 2008, 'The methionine connection: Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats', Hepatology, vol. 47, no. 2, pp. 659-667. https://doi.org/10.1002/hep.22037
Distrutti, Eleonora ; Mencarelli, Andrea ; Santucci, Luca ; Renga, Barbara ; Orlandi, Stefano ; Donini, Annibale ; Shah, Vijay ; Fiorucci, Stefano. / The methionine connection : Homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. In: Hepatology. 2008 ; Vol. 47, No. 2. pp. 659-667.
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AU - Renga, Barbara

AU - Orlandi, Stefano

AU - Donini, Annibale

AU - Shah, Vijay

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