Portal Hypertension in Liver Cirrhosis and Drug Therapy

由于肝硬化患者的肾素和血管紧张素水平升高，因此研究血管紧张素转换酶（ACE）抑制剂对门静脉血流动力学的影响是合乎逻辑的。此外，鉴于某些前列腺素（PG）可能参与调节肝脏阻力，甚至维持高动力状态的证据，需要更多的研究PG对肝脏和门静脉血流动力学的影响。测定动物模型和肝硬化患者的体循环（S）和门静脉循环（P）中前列腺素水平。在两种实验动物模型（CCl_4诱导的肝硬化大鼠（LC大鼠）和2周部分结扎诱导的门脉高压大鼠（PH大鼠））和对照组（C大鼠）中，测定了PG的稳定代谢产物6-酮-甘草甜素F_<1alpha>（6 KPG），其代谢产物为PGI_2，一种由PGI_2和PGI_2组成的代谢产物6-酮-甘草甜素。 ...更多信息 用兔抗血栓素A_2（TXA_2）放射免疫测定法测定血栓素B_2（TXB_2）。LC大鼠（S，2008 <plus-minus>549 pg/ml ; P，4802 654 pg/<plus-minus>ml）S和P循环中的6 KPG浓度比C大鼠（S，1116 <plus-minus>186 pg/ml ; P 983 <plus-minus>177 pg/ml（平均<plus-minus>SE））高约2和5倍（p&lt;0.05）。门静脉组织6 KPG在LC和PH组明显高于C组（分别为<plus-minus>255.36，<plus-minus>415.43，142.23pg<plus-minus>/mgWW）。LC大鼠S、P TXB_2浓度分别为3059 <plus-minus>± 1309 pg/ml和2315 ± <plus-minus>633 pg/ml，均高于PH大鼠（S，1243 ± 100 pg/ml）。(]178 P，未获得）和C大鼠（S，343（± SD）。[)63 P，417（± SD）。[)65 pg/ml）。模型组与C组大鼠组织中TXB_2含量无显著性差异。在临床研究中，我们收集了11例血小板减少性紫癜患者的血液样本。6 P循环的KPG和TXB_2水平显著高于S循环（P&lt;0.01），分别为S循环的10倍和14倍。[)31和484（]SY. [)192 P，4（±）μ g/ml。[)1和50（]SY. ±. [)8 pg/ml。这些结果表明，肝硬化门脉循环中PG，尤其是PGI_2的产生受到刺激，并可能参与门脉内压的升高。依那普利以10 mg的剂量口服给药8天。结果，我们观察到依那普利的临床有利的肾脏作用，即它显著增加肌酐清除率并产生相当大的尿钠排泄。提示依那普利是一种血管紧张素转换酶抑制剂，可作为治疗伴有周围性水肿和腹水的前列腺癌的有效药物之一。少

Because renin and angiotensin levels are increased in patients with liver eirrhosis, it could be logical to investigate the effects of angiotensin converting enzyme(ACE)inhibitors on portal hemodynamics. Additionaly, given the evidences that some prostaglandin(PG)may be involved in regulation of hepatic resistance and perhaps even in maintenance of the hyperdynamic state, more studies of PG effects on hepatic and portal hemodynamics are warranted.Because of few studies investigated the above these issues, we started to investigate the renin, angiotensin II, catecholamines, and prostanoids levels both in systemic (S) and portal (P) blood circulations from animal models and the patients with liver cirrhosis. In two experimetal animal models (the rats with CCl_4-induced liver cirrhosis (LC rat) and the rats with portal hypertension induced by 2 weeks partial ligation (PH rat)) and control (C) rats, we measured the stable PG metabolites 6-keto-prostagiandin F_<1alpha> (6KPG), from PGI_2, a … More nd thromboxane B_2 (TXB_2), from TXA_2 by radioimmunoassay employing rabbit-antibody. The 6KPG concentrations in tge S and P circulations were approximately 2 and 5 times higher (p<0.05) in LC rats(S, 2008 <plus-minus>549 pg/ml ; P, 4802<plus-minus>654 pg/ml) than in C rats (S, 1116<plus-minus>186 pg/ml ; P 983<plus-minus>177 pg/ml (mean<plus-minus>SE)). The tissue 6KPG of the portal vein was significantly higher in LC and PH rats than in C rats (255<plus-minus>36, 415<plus-minus>43, 142<plus-minus>23 pg/mgWW, respectively). The S and P TXB_2 concentrations were higher in LC rats(S, 3059<plus-minus>1309 pg/ml ; P, 2315<plus-minus>633 pg/ml) than in PH-rats (S, 1243(]SY.+-. (]178 pg/ml ; P, not obtained) and C rats (S, 343(]SY.+-.[)63 pg/ml ; P, 417(]SY.+-.[)65 pg/ml). The tissue TXB_2 levels did not differ between the model rats and the C rats. In the clinical study, we collected the PG's blood samples from 11 cirrhotic patients. 6KPG and TXB_2 levels in the P circulation were significantly (p<0.01) higher than (10 and 14 times) those in the S circulation : 57(]SY.+-.[)31 and 484(]SY.+-.[)192 pg/ml in P, 4(]SY.+-.[)1 and 50(]SY.+-.[)8 pg/ml in S, respectively. These results indicated that production of PG, particularly PGI_2, is stimulated in the portal circulation in liver cirrhosis and could be involved in the elevation of intraportal pressure.In the second step, we investigated the renal effects of an ACE inhibitor, enalapril in ten patients with liver cirrhosis. Enalapril was administered orally at the dose of 10 mg for eight days. As a result we observed clinically favorable renal effects of enalapril, that is, it increased creatinine clearance markedly and produced considerable natriuresis. This results suggested that enalapril, a ACE inhibitor, may be one of tools for the treatment of cirrhotic condition complicated with peripheral edema and ascites. Less