Aliskiren reduces portal pressure in cirrhotic rats
Aliskiren reduces portal pressure in cirrhotic rats
复制标题
阿利吉仑可降低肝硬化大鼠的门静脉压力
DOI：
10.1111/j.1478-3231.2011.02695.x
复制
发表时间：
2012
影响因子：
6.7
通讯作者：
Shou
中科院分区：
文献类型：
--
作者：
Ching;Hui;Wen‐Shin Lee;Sung;F. Lee;Han‐Chieh Lin;Jing;Shou
致编辑：越来越多的证据表明，肾素血管紧张素系统（RAS）参与肝纤维化和门静脉高压症的发病机制。在实验性肝损伤中，肝内RAS组分显著上调（1）。激活RAS可增加肝内血管紧张素II，进而刺激转化生长因子B-1介导和加重肝纤维化（2）。因此，RAS的操作可能对肝硬化患者具有潜在的治疗益处。阿利吉仑（2（S），4（S），5（S），7（S）-N-（2-氨基甲酰基-2-甲基丙基）-5-氨基-4-羟基-2，7-二异丙基-8-[4-甲氧基3-（3-甲氧基丙氧基）苯基]-辛酰胺半富马酸盐）是一种直接的肾素抑制剂，可阻断RAS上游并降低血压（3）。除了降低动脉血压的作用外，阿利吉仑还被证明可以增加内皮型一氧化氮合酶（eNOS）的生物合成（4）。我们进行了这项初步研究，以评估阿利吉仑治疗对胆总管结扎（BDL）诱导的胆汁淤积大鼠的影响。采用BDL诱导的继发性胆汁性肝硬化雄性Sprague-Dawley大鼠进行实验。BDL大鼠接受皮下注射20 mg/kg/天阿利吉仑或蒸馏水（对照）治疗10天（从BDL手术后第33天至第42天），然后测量全身和门静脉血流动力学以及肾脏和肝脏生物化学。阿利吉仑给药组和对照组之间无大鼠死亡。阿利吉仑给药组和对照组的体重和心率相似（表1）。长期阿利吉仑治疗显著降低平均动脉压和门静脉压。两组患者的心率、谷丙转氨酶、谷草转氨酶、总胆红素、肌酐水平均无差异。据我们所知，这是第一次阿利吉仑直接抑制肾素诱导全身血管舒张，降低门静脉压力在BDL诱导的大鼠。阿利吉仑的全身动脉和门静脉扩张效应可能来自全身和门静脉阻力的降低或内脏血流量的减少，这需要进一步研究。阿利吉仑治疗后，肝和肾生化未恶化，这意味着长期阿利吉仑治疗不会引起严重的肝和肾损伤。但对阿利吉仑治疗后肝内及侧支血管阻力、内脏血流量、肾血流量及肾小球滤过率的影响尚需进一步研究。阿利吉仑作为原型药物主要通过肝胆途径消除，在较小程度上通过细胞色素P450 3A 4的氧化代谢消除（5）。Vaidynnathan等人报告称，肝功能损害不会影响阿利吉仑的药代动力学，也不会加重阿利吉仑治疗后肝功能的恶化（5）。同样，本研究还证明，BDL诱导的大鼠中阿利吉仑给药组和对照组之间的肝脏生化无显著差异。血管紧张素II与动态和静态肝内阻力增加有关，血管紧张素受体阻滞剂抑制血管紧张素II可能
To the Editor: Emerging evidences show that the renin angiotensin system (RAS) takes part in the pathogenesis of liver fibrosis and portal hypertension. There is marked upregulation of intrahepatic RAS components in experimental liver injury (1). Activation of RAS could increase intrahepatic angiotensin II and then stimulate transforming growth factor b-1 to mediate and exacerbate liver fibrosis (2). Therefore, manipulations of the RAS could have potential therapeutic benefits for patients with liver cirrhosis. Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate) is a direct renin inhibitor which blocks the upstream of RAS and lowers blood pressure (3). Apart from the arterial blood pressure-lowering effect, aliskiren has been demonstrated to increase endothelial nitric oxide synthase (eNOS) biosynthesis (4). We conducted this preliminary study to evaluate the effects of aliskiren treatment on the common bile duct ligated (BDL)induced cirrhotic rats. Male Sprague-Dawley rats with secondary biliary cirrhosis induced by BDL were used for experiments. BDL rats received either subcutaneously injection of 20 mg/kg/day aliskiren or distilled water (control) treatments for 10 days (from day 33 to day 42 after a BDL operation), and followed by measurements of systemic and portal hemodynamics, and renal and liver biochemistries. There was no mortality of rats between the aliskiren-treated and control groups. The body weights and heart rates were similar between aliskiren-treated and control groups (Table 1). Chronic aliskiren treatment significantly reduced mean arterial pressure and portal pressure. There were no differences in the heart rates and levels of alanine transaminase, aspartate transaminase, total bilirubin and creatinine between these two groups. It is the first time, to our knowledge, that direct renin inhibition by aliskiren induces systemic vasodilatation and reduces portal pressure in BDL-induced cirrhotic rats. The systemic arterial and portal hypotensive effects of aliskiren may come from a reduction of systemic and portal resistance or a decrease of splanchnic blood flow, and it warrants further investigation. The hepatic and renal biochemistries are not exacerbated after aliskiren treatments which imply chronic aliskiren treatment does not elicit a major hepatic and renal damage. However, further study to investigate the intrahepatic and collateral resistance, splanchnic blood flow, renal blood flow and glomerular filtration rate of cirrhotic rats after aliskiren treatment is necessary. Aliskiren is largely eliminated through the hepatobiliary route as an unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 3A4 (5). Vaidynnathan et al. have reported that hepatic impairment did not influence the pharmacokinetics of aliskiren and exacerbate liver function after aliskiren treatment in cirrhotic patients (5). Similarly, this current study also demonstrated that there was no significant difference in the liver biochemistry between the aliskiren-treated and control groups of BDLinduced cirrhotic rats. Angiotensin II is associated with increased dynamic and static intra-hepatic resistance, and inhibition of angiotensin II by angiotensin receptor blocker may
影响因子：
8.3
作者：
Imanishi, Toshio;Tsujioka, Hiroto;Akasaka, Takashi
通讯作者：
Akasaka, Takashi