Portal Hypertension in Liver Cirrhosis and Drug Therapy

由于肾素和血管紧张素水平在肝硬化患者中升高，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，鉴于有证据表明某些前列腺素（PG）可能参与肝抵抗的调节，甚至可能参与维持高动力状态，因此有必要对PG对肝脏和门静脉血流动力学的影响进行更多的研究。由于研究上述问题的研究较少，我们开始研究动物模型和肝硬化患者全身(S)和门静脉(P)血液循环中的肾素、血管紧张素II、儿茶酚胺和前列腺素水平。用兔抗体放射免疫法测定了ccl_4致肝硬化大鼠（LC大鼠）和2周部分结扎致门脉高压症大鼠（PH大鼠）和对照大鼠(C)中PG稳定代谢产物6-酮-前列腺素F_< 1α > (6KPG)和TXA_2中血栓素B_2 （TXB_2）的含量。LC大鼠tge S和P循环中的6KPG浓度（S, 2008 <正负>549 pg/ml； P, 4802<正负>654 pg/ml）比C大鼠（S, 1116<正负>186 pg/ml； P, 983<正负>177 pg/ml（平均<正负>SE））高约2倍和5倍（P <0.05）。LC和PH大鼠门静脉组织6KPG均显著高于C大鼠（255<正负>36,415<正负>43,142<正负>23 pg/mgWW）。LC大鼠S和P TXB_2浓度（S, 3059<正负>1309 pg/ml； P, 2315<正负>633 pg/ml）高于ph大鼠(S, 1243（]SY.+-）。（]178 pg/ml； P，未得到）和C大鼠(S, 343(]SY.+-。[)63 pg/ml；P 417 (SY。+ -。() 65 pg / ml)。组织TXB_2水平在模型大鼠和C大鼠之间无显著差异。在临床研究中，我们采集了11例肝硬化患者的PG血样。P循环中kpg和TXB_2水平分别比S循环高10倍和14倍（P <0.01）；[)31和484 [](]SY.+-。[] P, 4(]SY.+-。[)1和50(][+-]。[)8 pg/ml，分别为S。这些结果表明，肝硬化患者门静脉循环中PG尤其是PGI_2的产生受到刺激，可能与门静脉内压力升高有关。在第二步，我们研究了ACE抑制剂依那普利对10例肝硬化患者的肾脏影响。依那普利以10毫克的剂量口服8天。结果，我们观察到依那普利在临床上良好的肾效应，即显著增加肌酐清除率并产生可观的尿钠。这一结果提示依那普利，一种ACE抑制剂，可能是治疗肝硬化并发周围性水肿和腹水的工具之一。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