Distrutti Eleonora, Mencarelli Andrea, Santucci Luca, Renga Barbara, Orlandi Stefano, Donini Annibale, Shah Vijay, Fiorucci Stefano
Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy.
Hepatology. 2008 Feb;47(2):659-67. doi: 10.1002/hep.22037.
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.
Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.
肝硬化肝脏肝内阻力增加是由内皮功能障碍以及两种气体血管舒张剂一氧化氮（NO）和硫化氢（H₂S）生成受损所致。同型半胱氨酸是一种含硫氨基酸和H₂S前体，由肝脏蛋氨酸代谢生成。在体循环中，高同型半胱氨酸血症会损害血管舒张以及内皮细胞生成NO。肝硬化患者血液中同型半胱氨酸水平升高很常见。在本研究中，我们证明，用同型半胱氨酸对正常肝脏进行急性肝灌注会损害甲氧明预收缩的正常肝脏中由乙酰胆碱诱导的NO生成和肝内血管舒张（7.3%±3.0%对26%±2.7%；P<0.0001）。在轻度饮食诱导的高同型半胱氨酸血症大鼠中，乙酰胆碱的血管舒张活性明显减弱，流量的增量增加导致灌注压的增加百分比高于对照肝脏。与正常大鼠相比，通过12周给予四氯化碳诱导肝硬化的动物对剪切应力的反应中灌注压增加的百分比更高（P<0.05），并且同型半胱氨酸进一步增强了肝内对流量增量增加的阻力（P<0.05）。在正常高同型半胱氨酸血症和肝硬化大鼠肝脏中，用硫化钠灌注肝脏可逆转由同型半胱氨酸引起的内皮功能障碍。同型半胱氨酸减少了肝血窦内皮细胞释放NO，还导致肝星状细胞收缩；这提示了一种双重作用机制，后一种作用可被H₂S抵消。
同型半胱氨酸引起的血管舒张受损和肝星状细胞收缩促成了门静脉高压的动态成分。
