The methionine connection: homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats.
Increased intrahepatic resistance in cirrhotic livers is caused by endothelial dysfunction and impaired formation of two gaseous vasodilators, nitric oxide (NO) and hydrogen sulfide (H(2)S). Homocysteine, a sulfur-containing amino acid and H(2)S 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 H(2)S.


CONCLUSIONS
Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D006710:Homocysteine / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000097:blood / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology*; D008103:Liver Cirrhosis / Q000097:blood / Q000503:physiopathology; D008297:Male; D008715:Methionine / Q000502:physiology*; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D006710:Homocysteine; D008715:Methionine; D000109:Acetylcholine; D006862:Hydrogen Sulfide