Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4)

AIM:To investigate effect of losartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCl(4); and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. METHODS AND RESULTS:Fifty male Sprague-Dawley rats, weighing (180 plus minus20)g, were randomized into five groups (control group, model group, and three losartan treated groups), in which all rats were given the subcutaneous injection of 40% CCl(4)(every 3 days for 6 weeks) except for rats of control group. Rats of losartan-treated groups were treated with losartan (20 mg/kg, 10 mg/kg, 5 mg/kg, daily gavage). After 6 weeks liver tissue and serum samples of all rats were examined. Serum hyaluronic acid (HA), procollagen type III (PC III) were detected by radioimmunoassays. van Giesion collagen staining was used to evaluate the extracellular matrix of rats with liver fibrosis. The expression of AT1 receptors, transforming growth factor-beta (TGF-beta), and alpha-smooth muscle actinalpha-SMA) in liver tissue were determined by immunohistochemical techniques. Compared with model group, serum ALT and AST of losartan-treated groups were significantly reduced (italic>t = 4.20,P < 0.01 and italic>t = 4.57,P < 0.01). Serum HA and PC III also had significant differences (italic>t = 3.53,P<0.01 and t=2.20, P<0.05). The degree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors, TGF-beta, and alpha-SMA in liver tissue.CONCLUSION:AT1 receptor antagonist, losartan, could limit the progression of the hepatic fibrosis induced by CCl(4). The mechanism may be related to the decrease in the expression of AT1 receptors and TGF-beta, ameliorating the injury of hepatocytes; activation of local renin-angiotensin system might relate to hepatic fibrosis; and during progression of fibrosis, activated hepatic stellate cells might express AT1 receptors.     

洛沙坦的药物基因组学研究进展

洛沙坦是常用的血管紧张素Ⅱ受体拮抗剂,在治疗高血压等心血管疾病中具有重要作用,临床实践发现不同个体对洛沙坦的反应差异大,研究表明遗传因素是导致洛沙坦疗效产生个体差异的重要因素之一。主要对洛沙坦基因遗传多态性的研究进展进行综述。     

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

At the time of writing this commentary (February 2020), the coronavirus COVID-19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS-CoV-2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.     

Safety, Tolerability, and Neurohormonal Changes of the Combination Captopril Plus Losartan in the Early Postinfarction Period: A Pilot Study

Suppression of formation of angiotensin II (A-II) is thought to be a major contributor to the hemodynamic response to angiotensin-converting enzyme inhibition (ACE-in) therapy. However, angiotensin II (A-II) plasma levels may rebound during ACE-in treatment. The study sought to verify the feasibility, safety, and tolerability of the combination of captopril (75 mg/d) plus losartan (25 mg/d). We also wished to establish whether the combination was able to avoid the increase of angiotensin II resulting from losartan treatment in early postinfarction phases of reperfused anterior acute myocardial infarction (AMI). Forty-four patients, hospitalized for suspected anterior AMI within 4 hours from the onset of symptoms, suitable for thrombolysis (first episode), Killip class I-II and reperfused, receiving 75 mg/d of captopril within 3 days from admission, and with systolic blood pressure (BP) >120 mmHg were randomized (single-blind) into two groups: Group A included 22 patients (6 women and 16 men) and received captopril 75 mg/d and placebo. Group B included 22 patients (5 women and 17 men) and received captopril 75 mg/d within 3 days from admission plus losartan 12.5 mg, as the first dose, and 25 mg/d (BP >110 mmHg) successively. Norepinephrine (NE) and A-II levels were measured on the 3rd and 10th days after admission. The two groups were similar with regard to age, sex, creatinine kinase peak, ejection fraction, end-systolic volume, and risk factors. Group B (captopril plus losartan) showed a significant reduction of BP, from 124 ± 8.5 mmHg to 108 ± 6.4 mmHg, P < 0.001, at 10 days after admission. In group A, BP was 122 ± 9 mmHg, and 10 days after admission BP was 118 ± 11 mmHg. NE and A-II values did not show significant differences in basal samples. At 10 days after admission values were NE 298 + 90 versus 272 ± 86 pg/mL and A-II 6.07 ± 2.97 versus 5.29 ± 2.05 pg/mL for the two groups. Our data suggest, for the first time, that the combination of captopril plus losartan is feasible and does not produce serious side effects. When losartan was added to ACE-in treatment, there was no significant increase in A-II.     

氯沙坦和依那普利对原发性高血压患者肾功能的影响

目的　探讨血管紧张素Ⅱ受体拮抗剂 (AIRA)和血管紧张素转换酶抑制剂 (ACEI)对原发性高血压 (EH)患者肾功能的影响。方法　采用随机、单盲和平行对照方法 ,经 1周药物冲洗期及 2周安慰剂导入期后 ,6 0例EH患者 (EH组 )进行 16周治疗期 ,每日 1次口服氯沙坦 5 0mg(n =30 )或依那普利 5mg(n =30 ) ,4周后如舒张压 (DBP)≥ 90mmHg(1mmHg =0 133kPa)则剂量加倍。治疗后测量血压、心率 (HR)并记录症状、体征 ;并行 2 4h动态血压监测(ABPM) 1次。治疗前后分别测定血清肌酐 (Cr)、尿素氮 (BUN)、内生肌酐清除率 (Ccr)和 2 4h尿蛋白 (UTP)、白蛋白(Alb) ,尿α1及 β2 微球蛋白 (α1 MG和β2 MG)的排泄率。 2 0例健康体检者作为对照组。结果　⑴两组药物均能明显降低血压 (P <0 0 0 1)。⑵治疗前EH组患者Ccr显著低于对照组 ,尿α1 MG和 β2 MG及UTP、Alb显著高于对照组 ,且上述指标改变程度与EH的病程相关。⑶治疗 16周后 ,氯沙坦和依那普利均能显著降低尿UTP、Alb ,尿α1 MG和β2 MG ,其中病程较长者 ,下降幅度较大。⑷咳嗽发生率氯沙坦组 (6 7% )明显低于依那普利组 (2 6 7% ) (P <0 0 1)。结论　⑴EH患者早期即有肾功能损害 ,且随病程延长损害加重。⑵氯沙坦可减轻和延缓高血压引起的肾功能损害 ,且病     

Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice

Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor–beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency.     

槟榔碱诱导人脐静脉内皮细胞表达α-SMA的实验研究

目的：检测氯沙坦干预下、槟榔碱诱导的人脐静脉内皮细胞（HUVECs）表达α-SMA的情况。方法：用不同浓度槟榔碱刺激HUVECs,采用免疫细胞印迹法检测各组HUVECs中α-SMA的表达。再以固定槟榔碱浓度诱导HUVECs,不同浓度氯沙坦干预,检测各组HUVECs中α-SMA的表达。结果：槟榔碱可诱导HUVECs表达α-SMA,经氯沙坦干预后α-SMA的表达受到一定抑制。结论：HUVECs经槟榔碱刺激后可转化为表达α-SMA的肌成纤维细胞。血管紧张素Ⅱ受体拮抗剂氯沙坦可部分抑制这种转化,提示血管紧张素Ⅱ及其受体参与了槟榔碱诱导的内皮-间充质转化。