阿利吉仑对高血压肾病小鼠肾的保护作用及其作用机制

目的探究阿利吉仑对高血压肾病小鼠的保护作用及其对磷脂酰肌醇激/蛋白激酶B(PI3K/Akt)信号通路和半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)表达的影响。方法用微渗泵灌注血管紧张素Ⅱ制备高血压小鼠肾病模型。按照体重将小鼠随机分为6组:假手术组、模型组和低、中、高3个剂量实验组(灌胃阿利吉仑12. 5,25. 0,50. 0 mg·kg^-1)与对照组(卡托普利30 mg·kg^-1),每组15只;造模后给药,每日1次,连续灌胃2周。以实时定量PCR法测定肾组织中胰岛素受体底物2(Irs2)、磷脂酰肌醇激酶-3(PI3K)、蛋白激酶B(Akt) mRNA表达;以免疫印迹法测定Irs2、PI3K、Akt与Caspase-3蛋白表达情况。结果给药4周,假手术组、模型组、对照组和高剂量实验组的PI3K mRNA表达分别为1. 14±0. 21,0. 34±0. 08,1. 07±0. 23和0. 96±0. 22;这4组的Akt mRNA表达分别为1. 23±0. 27,0. 45±0. 13,1. 05±0. 16和0. 91±0. 15,模型组与假手术组比较或高剂量实验组与模型组比较,差异均有统计学意义(均P <0. 05)。这4组的小鼠肾组织Caspase-3蛋白表达水平分别为0. 29±0. 06,1. 06±0. 13,0. 31±0. 06和0. 37±0. 08,模型组与假手术组比较或高剂量实验组与模型组比较,差异均有统计学意义(均P <0. 05)。结论阿利吉仑对高血压小鼠肾具有一定的保护作用,其机制可能与激活PI3K/Akt信号通路、抑制Caspase-3表达有关。     

Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice

Aim:

Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action.

Methods:

Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg⁻¹·d⁻¹, po), the autophagy inhibitor 3-methyladenine (10 mg·kg⁻¹ per week, ip) or the PKCβI inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY333531","term_id":"1257370768","term_text":"LY333531"}}LY333531 (1 mg·kg⁻¹·d-¹, po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.

Results:

TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while {"type":"entrez-nucleotide","attrs":{"text":"LY333531","term_id":"1257370768","term_text":"LY333531"}}LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, {"type":"entrez-protein","attrs":{"text":"CGP53353","term_id":"875191971","term_text":"CGP53353"}}CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.

Conclusion:

ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβI-ERK1/2-regulated autophagy.     

阿利吉仑——一种新型肾素抑制剂

肾素抑制剂作用于肾素-血管紧张肽系统(RAS)的第一限速步骤,不同于血管紧张肽转换酶抑制剂 (ACEI)及血管紧张肽Ⅱ受体拮抗药(ARB),提供了阻断RAS的全新途径。首个合成的新型非肽类肾素抑制剂——阿利吉仑,剂量依赖性抑制肾素活性,有效降低血压,疗效与ARB相近,安全性及不良反应与安慰剂相似,有望成为第一种用于治疗高血压以及其并发症的口服肾素抑制剂。     

新型肾素抑制剂阿利吉仑临床应用的研究进展

许多心血管疾病和肾脏疾病的病理生理过程都伴有肾素-血管紧张素-醛固酮系统（RAAS）的激活。在高血压的治疗方案中,血管紧张素转化酶抑制剂（ACEIs）和血管紧张素受体阻滞剂（ARBs）成为一线用药。长期以来肾素被认为是RAAS中最经典、最合乎逻辑的药物靶标,然而,首个肾素抑制剂阿利吉仑在2007年才被批准用于高血压疾病的治疗。近年来阿利吉仑良好的血压控制效果及脏器保护效应备受关注。因阿利吉仑能更完全地抑制RAAS,以其为基础的联合用药方案对于预防高血压并发症业已取得良好效果。本文就近年来阿利吉仑在临床应用中的研究进展进行综述。     

肾素抑制剂阿利克仑的药理与临床评价

阿利克仑是一种有效的肾素抑制剂,它比早期的肾素抑制剂口服吸收更好,而且半衰期很长,每日1次即可,是一种很有前途的新型降压药。长期数据还未公布。现对其药理作用、药动学、临床疗效及安全性等做一综述。     

Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study

Objective: The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP).

Research design and methods: After 4-week placebo, 120 outpatients with grade 1 – 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed.

Results: Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01).

Conclusions: Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.     

阿利克仑的合成

对肾素抑制剂阿利克仑的合成工艺进行研究。采用化学拆分法分别制备了合成阿利克仑的手性片段化合物1和2,再经5步汇聚式合成得到目标产物阿利克仑,总收率15.6%。中间体和目标产物经熔点、NMR、ESI-MS表征。所采用的工艺路线光学纯度可控,收率较好,操作简便,无需特殊试剂和复杂的分离纯化过程,具备一定的工业化生产潜力。     

Protective effect of a direct renin inhibitor in acute murine model of cardiotoxicity and nephrotoxicity

This study aimed to investigate the possible protective effects of aliskiren against doxorubicin (DXR)‐induced cardiorenal injury and to identify the mechanisms involved. Intraperitoneal administration of DXR (15 mg/kg, body weight, as a single dose) caused significant induction in the levels of angiotensin I, caspase‐3, lactate dehydrogenase (LDH), lipid peroxidation malondialdehyde (MDA), urea, and creatinine. Concomitant decline in the levels of albumin and total protein in plasma, reduction in reduced glutathione (GSH), and antiperoxidative enzyme superoxide dismutase (SOD) levels followed by ultrastructural alterations in the myocardial and renal tissues were also observed. Oral administration of aliskiren (100 mg/kg, for a period of 14 days) significantly prevented all these DXR‐induced adverse effects and maintained the rats near to normal status. However, telmisartan (10 mg/kg) pretreatment has shown slight protection in DXR‐induced renal injury as evidenced by broadening of podocyte foot process and narrowing of slit pore diameter. The results of aliskiren were compared with telmisartan which was used as reference in this study. These results suggested that aliskiren has protective effects against acute model of DXR‐induced cardiotoxicity and nephrotoxicity, implying that plasma renin activity plays a role in DXR‐induced cardio‐renal injury.     

直接肾素抑制剂的临床应用前景

肾素-血管紧张素-醛固酮系统是药物治疗心血管系统疾病的关键作用靶点。阻断肾素-血管紧张素系统的病理生理作用可以从三个位点进行：血管紧张素转换酶抑制剂、血管紧张素Ⅱ受体拮抗剂和肾素抑制剂。近年研究表明直接肾素抑制剂比血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂具有更多的潜在获益和更好的耐受性。现就直接肾素抑制剂药物阿利吉伦的应用前景进行综述。