The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis.
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 micromol/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.
Fiorucci
Stefano
S
Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia, Italy. fiorucci@unipg.it
Antonelli
Elisabetta
E
Mencarelli
Andrea
A
Orlandi
Stefano
S
Renga
Barbara
B
Rizzo
Giovanni
G
Distrutti
Eleonora
E
Shah
Vijay
V
Morelli
Antonio
A
D000818:Animals; D001483:Base Sequence; D002252:Carbon Tetrachloride Poisoning / Q000503:physiopathology / Q000517:prevention & control; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors; D017931:DNA Primers; D004195:Disease Models, Animal; D005905:Glyburide / Q000627:therapeutic use; D006862:Hydrogen Sulfide / Q000494:pharmacology* / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008102:Liver Circulation / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D018377:Neurotransmitter Agents; D003542:Cystathionine gamma-Lyase; D005905:Glyburide; D006862:Hydrogen Sulfide