Effects of AT1 receptor antagonist, Iosartan, on rat hepatic fibrosis induced by CCl4

AIM To investigate effect of Iosartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCI4; and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. M~THODS AND RESULTS Fifty male SpragueDawley rats, weighing (180 ± 20) g, were randomized into five groups (control group, model group, and three Iosartan treated groups ), in which all rats were given the subcutaneous injection of 40% CCl4 (every 3 days for 6 weeks) except for rats of control group. Rats of Iosartantreated groups were treated with Iosartan (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 (TGFβ), and alpha-smooth muscle actin (α-SMA) in liver tissue were determined by immunohistochemical techniques. Compared with model group, serum ALT and AST of Iosartantreated groups were significantly reduced (t = 4.20, P < 0.01 and t = 4.57, P < 0.01 ). Serum HA and PC Ⅲ also had significant differences (t = 3.53, P<0.01 and t=2.20, P<0.05). The degree of fibrosis was improved by Iosartan and correlated with the expressions of AT1 receptors, TGF-β, and α-SMA in liver tissue. CONCLUSION AT1 receptor antagonist, Iosartan, could limit the progression of the hepatic fibrosis induced by CCl4. The mechanism may be related to the decrease in the expression of AT1 receptors and TGF-β, 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.     

The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis:effects of RAS inhibitors on hepatic fibrosis induced by CCl(4)

AIM:To assess the effect of ACE inhibitor and Ang II type 1 (AT1) receptor antagonist in preventing hepatic fibrosis caused by CCl(4) administration in rats;to investigate whether or not there are expression of AT 1 receptors on hepatic stellate cells; and to observe the effect of Ang II on proliferation and ECM synthesis of cultured HSCs.METHODS:Studies were conducted in male Sprague-Dawley rats. Except for the hepatofibrotic model group and the control group, in three treated groups, either enalapril (5mg/kg), or losartan (10mg/kg), or enalapril + losartan were given to the fibrotic rats by daily gavage, and saline vehicle was given to model and normal control rats. After 6 weeks, liver fibrosis was assessed directly by hepatic morphometric analysis, which has been considered the gold standard for the quantification of fibrosis. The expressions of AT 1 receptors and (alpha-mooth muscle actin,alpha-SMA) in liver tissue or isolated hepatic stellate cells (HSCs) were detected by immunohistochemical techniques. The effect of Ang II on HSC proliferation was determined by MTT method. Effect of Ang II on collagen synthesis of HSCs was determined by (3)H-proline incorporation.RESULTS:Contrasted to the fibrosis in rats of the model group, groups of rats treated with either enalapril or losartan, or a combination of two drugs showed a limited expansion of the interstitium (4.23 plus minus 3.70 vs 11.22 plus minus 4.79, P<0.05), but no difference was observed among three treated groups (5.38 plus minus3.43, 4.96 plus minus 2.96, 4.23 plus minus 2.70, P>0.05). Expression of AT 1 receptors was found in fibrotic interstitium of fibrotic rats, whereas in normal control rats they were limited to vasculature only to a very slight degree. AT 1 receptors were also expressed on activated HSCs in the culture. At concentrations from 10(-9) to 10(-5)mol/L, Ang II stimulated HSC proliferation in culture in a dose dependent manner. Increasing Ang II concentrations produced corresponding increases in (3)H-proline incorporation. Differences among groups were significant.CONCLUSION:Angiotensin converting enzyme inhibitors and AT 1 blocker may slow the progression of hepatic fibrosis;activated HSCs express AT 1 receptors, and Ang II can stimulate the proliferation and collagen synthesis of HSCs in a dose-dependent manner; and activation of RAS may be related to hepatic fibrogenesis induced by CCl(4).     

Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis

BACKGROUND: The renin-angiotensin system may be implicated in the subtle sodium handling abnormality in preascitic cirrhosis. AIMS: To assess the role of angiotensin II in sodium homoeostasis in preascitic cirrhosis, using losartan, its receptor antagonist. PATIENTS: Nine male, preascitic cirrhotic patients, and six age matched, healthy male controls. METHODS: A dose response study using 2.5, 5, 7.5, and 10 mg of losartan was performed on a daily 200 mmol sodium intake, followed by repeat studies with the optimal dose, 7.5 mg of losartan, to determine its effects on systemic and renal haemodynamics, renal sodium handling, and neurohumoral factors. RESULTS: Preascitic cirrhotic patients had significantly reduced baseline urinary sodium excretion compared with controls (154 (8) versus 191 (12) mmol/day, p<0.05), associated with significantly reduced systemic angiotensin II levels (6.0 (1.7) versus 39.5 (10.0) pmol/l, p=0.002). Losartan 7.5 mg normalised renal sodium handling in the preascitic cirrhotic patients (202 (12) mmol/day, p=0.05 versus baseline), without any change in systemic or renal haemodynamics, but with significantly increased systemic angiotensin II levels (7.8 (2.3) pmol/l, p=0.05 versus baseline). Losartan had no effect on renal sodium handling in controls. CONCLUSIONS: In preascitic cirrhotic patients, the subtle renal sodium retention, paradoxically associated with low systemic neurohumoral factor levels, is improved with low dose losartan, suggesting the involvement of angiotensin II via its direct action on the renal tubule.     

纤维化分期对大鼠肝组织血管紧张素Ⅱ AT1受体表达的影响

目的探讨肝组织中血管紧张素Ⅱ1型受体的表达与四氯化碳诱导大鼠肝纤维化分期的相关性。方法肝组织HE染色检测病理改变,免疫组化技术检测血管紧张素Ⅱ AT1受体在肝组织的表达,应用计算机进行灰度扫描,采用德国Leica公司生产的Qwiuv图像分析软件测定每一样本的灰度值,根据纤维化不同分期的灰度值进行统计学处理。结果随着大鼠肝纤维化加重,血管紧张素Ⅱ AT1受体在肝组织的表达增多,经统计学处理各期之间差异有统计学意义。结论纤维化分期与大鼠肝组织血管紧张素Ⅱ AT1受体的表达有明显的相关性。     

Effects of perindopril and valsartan on expression of transforming growth factor-beta-Smads in experimental hepatic fibrosis in rats

BACKGROUND: Previous studies have shown that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of hepatic fibrosis, and blockers of the RAS may be active as an antifibrogenic goal. However, the potential role of RAS inhibition on expression transforming growth factor (TGF)-beta-Smads in hepatic fibrosis remains unknown. The aim of this study was to investigate the effect and mechanism of an angiotensin-converting enzyme inhibitor (perindopril) and an angiotensin II receptor blocker (valsartan) on TGF-beta1 and TGF receptor II (TRII) mRNA, Smad3 and Smad7 in fibrotic hepatic livers in rats. METHODS: Sixty Wistar rats were randomly divided into four study groups (n = 15 for each group), including normal controls, hepatic fibrosis models, and two treated groups with either perindopril or valsartan, starting from the fourth week after being exposed to carbon tetrachloride (CCl(4)) for 4 weeks. The levels of TGF-beta and TRII mRNA in liver tissue were analyzed by RT-PCR. The expressions of TGF-beta1, Smad3 and Smad7 in liver tissues were evaluated by immunohistochemistry. The liver histopathology was examined by hematoxylin and eosin (HE) staining and by electron microscopy, respectively. The liver function and serum hyaluronic acid were also assayed by biochemistry and radioimmunoassay. RESULTS: Compared with the hepatic fibrosis models, the levels of TGF-beta1, TRII mRNA and the expression Smad3 significantly decreased in the two treated groups, and the expression of Smad7 was significantly increased in the liver of rats treated with perindopril or valsartan (P < 0.05 or P < 0.01). The histological changes and ultrastructure of fibrotic liver, liver function and hyaluronic acid also remarkably improved in the treated rats. CONCLUSIONS: The angiotensin-converting enzyme inhibitors perindopril and valsartan have a protective effect on liver injury and can ameliorate hepatic fibrosis in rats induced by CCl(4). The mechanisms may be associated with their effects of down-regulating TGF-beta1, TRII mRNA and smad3, and up-regulating Smad7.     

Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases

BACKGROUND AND AIMS: Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II type I receptor (AT1R) antagonists are commonly used as a treatment for hypertension. Recent experimental and population studies have suggested that these agents may exert an inhibitory effect on malignancy, possibly through anti-angiogenic pathways. The aim of this study was to investigate the effect of an ACE-I (captopril) and an AT1R antagonist (irbesartan) in colorectal cancer liver metastases. METHODS: The effect of captopril and irbesartan on tumor growth was investigated in a mouse model using quantitative stereological and histological analysis. Tumor microcirculation was assessed by microvascular resin casting. A survival study was also carried out. RESULTS: Both captopril and irbesartan markedly decreased tumor growth when compared to control (P = 0.003 and P = 0.004, respectively). However, there was no significant difference in survival or tumor necrosis for either of the drugs. Tumor microvasculature exhibited a reduction in central microvascular density, with constriction and tapering of vessels. CONCLUSION: Captopril and irbesartan caused a marked reduction in volume of colorectal cancer liver metastases and caused changes in tumor microvasculature. However, there was no difference in percentage tumor necrosis or improvements in survival. Further investigation is needed to identify the mode of action of these agents.     

激动素抗大鼠肝纤维化的实验研究

目的:研究激动素对实验性肝纤维化的影响,探讨作用机制。方法:用CCl4诱导形成大鼠肝纤维化模型,使用0.1%激动素溶液0.5ml.100g-1.d-1,背部皮下注射,治疗12周,设正常对照组和模型组。血清ALT用全自动生化分析仪检测,血清透明质酸(HA)、层黏连蛋白(LN)、Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(CⅣ)含量用RIA方法检测。肝组织学检查:采用苏木精-伊红染色观察肝组织炎症和纤维化程度。结果:激动素组ALT水平与模型组ALT水平分别为(57.40±17.49)U/L和(84.70±31.85)U/L,两组比较差异有显著性意义(P<0.05)。激动素组LN和CⅣ含量分别为(29.25±6.67)ng/ml和(14.84±5.84)ng/ml,较模型组(37.18±10.06)ng/ml、(35.69±30.84)ng/ml明显降低(P<0.05);激动素组HA和PCⅢ含量分别为(136.25±76.83)ng/ml和(11.43±3.67)ng/ml,较模型组(168.55±56.19)ng/ml、(14.64±8.00)ng/ml有不同程度降低,但无统计学意义。组织学检测结果表明,模型组肝脏炎症和纤维化程度明显高于激动素组。结论:激动素对实验性大鼠肝纤维化具有抑制作用。     

Effects of AT1 receptor antagonist therapy in patients with severe heart failure pretreated with angiotensin-converting enzyme inhibitors

BACKGROUND:

The efficacy of angiotensin-converting enzyme (ACE) inhibitors is well documented in the treatment of chronic severe heart failure. Because pharmacological mechanisms of angiotensin II type 1 (AT1) receptor antagonists differ from the effects of ACE inhibitors, an additional positive effect can be expected by combining these drugs.

METHODS:

Sixty patients (mean age 68.3±10.0 years) with severe chronic heart failure receiving long term medication with digitalis, diuretics, ACE inhibitors and in part beta-blockers (68.3%) were randomly assigned after clinical recompensation to three groups: additional therapy with eprosartan (477.5±143.7 mg/day), telmisartan (65.9±17.7 mg/day) and control group according to a prospective study design. Hemodynamic measurements by impedance cardiography were performed before and during the observation period (9.6±3.4 days).

RESULTS:

Additional sartan treatment resulted in an improvement in cardiac output from 2.32±0.69 L/min to 3.12±1.24 L/min (P=0.003) in the eprosartan group and from 2.24±0.59 L/min to 2.76±0.91 L/min (P=0.001) in the telmisartan group; cardiac output in the control group did not increase. Furthermore, a significant decrease in total peripheral resistance was observed during treatment with eprosartan (23%, P=0.002) and telmisartan (18%, P=0.002). In the subgroup receiving combined therapy with beta-blockers, ACE inhibitors and AT1 antagonists, a significant increase in cardiac output was also observed.

CONCLUSIONS:

The additional treatment with AT1 receptor antagonists resulted in an increase in the cardiac output and a decrease in the peripheral resistance. This beneficial effect may be due to the additional property of sartans to block the interaction of locally and non-ACE-generated angiotensin II with their respective vascular and myocardial AT1 receptors.     

Rating of CCl(4)-induced rat liver fibrosis by blood serum glycomics

BACKGROUND: Non-invasive staging of human liver fibrosis is a desirable objective that remains under extensive evaluation. Animal model systems are often used for studying human liver disease and screening antifibrotic compounds. The aim of the present study was to investigate the potential use of serum N-glycan profiles to evaluate liver fibrosis in a rat model. METHODS: Liver fibrosis and cirrhosis were induced in rats by oral administration of CCl(4). Liver injury was assessed biochemically (alanine aminotransferase [ALT] activity, aspartate aminotransferase [AST] activity and total bilirubin) and histologically. The N-glycan profile (GlycoTest) was performed using DNA sequencer-assisted-fluorophore-assisted carbohydrate electrophoresis technology. In parallel, the effect of cotreatment with antifibrotic interferon-gamma (IFN-gamma) was studied. RESULTS: The biopsy scoring system showed that CCl(4) induced early fibrosis (F < 1-2) in rats after 3 weeks of treatment, and cirrhosis (F4) after 12 weeks. Significant increases in ALT activity, AST activity and total bilirubin levels were detected only after 12 weeks of CCl(4) treatment. GlycoTest showed three glycans were significantly altered in the CCl(4)-goup. Peak 3 started at week 6, at an early stage in fibrosis development (F < 1-2), whereas peaks 4 and 5 occurred at week 9, at which time mild liver fibrosis (F = 1-2) had developed. The changes in the CCl(4)-IFN-gamma group were intermediate between the CCl(4)- and the control groups. CONCLUSION: The GlycoTest is much more sensitive than biochemical tests for evaluating liver fibrosis/cirrhosis in the rat model. The test can also be used as a non-invasive marker for screening and monitoring the antifibrotic activity of potential therapeutic compounds.     

CV-11974, angiotensin II type I receptor antagonist, reduces the severity of indomethacin-induced rat enteritis

The aim of the present study was to examine the effect of angiotensin II type I receptor antagonist, CV-11974, on indomethacin-induced small intestinal injury in rats. Single administration of indomethacin provoked severe inflammatory lesions in the small intestine. The levels of thiobarbituric acid-reactive substances (TBARS), myeloperoxidase (MPO) activities and cytokine-induced neutrophil chemoattractant-1 (CINC-1) in the intestinal mucosa significantly increased in the indomethacin-treated group compared with the sham group. In addition, the angiotensin II type I receptor was increased in the small intestine after the administration of indomethacin. The development of intestinal lesions in response to indomethacin was prevented by pretreatment with CV-11974 together with significant suppression of the increased level of TBARS, MPO activities and CINC-1. These results indicate that CV-11974 protected against the small intestinal damage elicited by indomethacin, which suggests that angiotensin II/AT1 receptor interaction is involved in the pathogenesis of the intestinal inflammation associated with oxidative stress.     

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist

Introduction Blockade of the AT₁ angiotensin II (Ang II) receptor has been shown to provide antihypertensive effects. However, whether AT₁ Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear.Methods and results Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n=13) and guinea pig (n=9) myocardial preparations in the presence of the specific AT₁ Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mol/L of valsartan, resting membrane potential increased from baseline in both rat (–82.3±4.1 vs –76.8±5.8 mV, p<0.05) and guinea pig (–81.6±2.9 vs –76.9±2.0 mV, p<0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7±1.4 vs 80.0±5.6 ms, p<0.05) and ventricular (131.1±8.1 vs 118.7±8.3 ms, p<0.05) myocardium following exposure to 500 mol/L of valsartan. In a separate series of experiments Ang II (1.0 mol/L) had no effect on atrial or ventricular action potential characteristics in either species.Conclusion Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.     

福辛普利和氯沙坦对自发性高血压大鼠Toll样受体4表达的影响

目的:研究福辛普利(fosinopril)和氯沙坦(losartan)干预自发性高血压大鼠(SHR)后Toll样受体4(TLR-4)、NF-κB、IL-6、TNF-α等基因的表达,探讨其在治疗高血压肾损伤中的作用机制。方法:20只22周龄雄性SHR,随机分为4组(5只/组):高血压组(SHR模型组),Fosinopril组[10mg/(kg.d)],Losartan组[50mg/(kg·d)],联合治疗组[fosinopril 10mg/(kg·d) losartan50mg/(kg·d)];另22周龄雄性WKY大鼠5只为正常对照,共喂养8周。检测各组大鼠体重、尾动脉收缩压、24h尿蛋白定量(Upro)、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG酶)、血尿素氮(BUN)及血肌酐(SCr)等。HE染色观察大鼠肾脏病理改变,RT-PCR检测TLR-4、IL-6、TNF-αmRNA表达;WesternBlot检测TLR-4蛋白及NF-κB核蛋白表达;ELISA检测血清IL-6及TNF-α水平。结果:SHR肾脏出现高血压肾损伤的病理特征,并伴有小管间质的炎性细胞浸润。Fosinopril、Losartan干预8周后,肾脏病理改变减轻,SHR收缩压、Upro及尿NAG酶均明显降低(P<0.05)。TLR-4 mRNA及蛋白表达均明显下调(P<0.05)。NF-κB核蛋白表达显著受抑制(P<0.05)。血清IL-6及TNF-α水平显著下降(与模型组比较均P<0.05)。联合治疗组较单药组无明显协同作用(P>0.05)。结论:Fosinopril和Losartan可下调TLR-4基因及相关炎症介质的表达,可能是其治疗高血压肾损伤的作用机制之一。     

Effects of transmitters and interleukin-10 on rat hepatic fibrosis induced by CCl4

AIM: To study the effects of transmitters ET, AgⅡ, PGI2,CGRP and GG on experimental rat hepatic fbrosis and the antifibrogenic effects of IL-10.METHODS: One hundred SD rats were randomly divided into 3 groups: control group (N): intraperitoneal injection with saline 2 ml.kg^-1 twice a week; the fibrogenesis group (C): intraperitoneal injection with 50 % CC14 2 ml.kg^-1 twice a week; IL-10 treated group (E): besides same dosage of CC14 given, intraperitoneal injection with IL-10 4 ug.kg^-1 from the third week. In the fifth, the seventh and the ninth week,rats in three groups were selected randomly to collect plasma and liver tissues. The levels of ET, AgⅡ, PGI2, CGRP and GG were assayed by radioimmunoassay (RIA). The liver fibrosis was observed with silver staining.RESULTS: The hepatic fibrosis was developed with the increase of the injection frequency of CC14. The ET, AgⅡ, PGI2, CGRP and GG levels in serum of group N were 71.84&#177;60.2 ng.L^-1,76.21&#177;33.3 ng.L^-1, 313.03&#177;101.71 ng.L^-1, 61.97&#177;21.4 ng.L^-1 and 33.62&#177;14.37 ng.L^-1, respectively; the levels of them in serum of group C were 523.30&#177;129.3 ng.L^-1, 127.24&#177;50.0 ng.L^-1,648.91&#177;357.29 ng.L^-1, 127.15&#177;62.0 ng&#183;L^-1 and 85.26&#177;51.83ng.L^-1, respectively; the levels of them in serum of group E were 452.52&#177;99.5 ng.L^-1, 90.60&#177;44.7 ng.L^-1, 475.57&#177;179.70ng.L^-1, 102.2&#177;29.7 ng.L^-1 and 38.05&#177;19.94 ng.L^-1, respectively.The histological examination showed that the degrees of the rats liver fibrosis in group E were lower than those in group C.CONCLUSION: The transmitters ET, AgⅡ, PGI2, CGRP and GG play a significant role in the rat hepatic fibrosis induced by CCl4, IL-10 has the antagonistic action on these transmitters and can relieve the degree of the liver fibrosis.     

Three-Month Effects of Candesartan Cilexetil, an Angiotensin II Type 1 (AT1) Receptor Antagonist, on Left Ventricular Mass and Hemodynamics in Patients with Essential Hypertension

Using cine magnetic resonance imaging (MRI) and echocardiography, we investigated the effects of candesartan cilexetil, a specific angiotensin II type 1 (AT1) receptor antagonist, on left ventricular (LV) mass and hemodynamics in patients with essential hypertension. Ten patients (four men and six women) with essential hypertension received candesartan cilexetil 2–8 mg/day orally for 8–12 weeks. After drug administration, systolic blood pressure (BP) decreased from 178.9 ± 17.2 mmHg (mean ± SD) to 150.2 ± 14.3 mmHg (P < 0.0001) and diastolic BP from 101.4 ± 6.5 mmHg to 87.8 ± 11.9 mmHg (P = 0.0021). Both MRI and echocardiography revealed a significant decrease in LV mass index (LVMI) after candesartan cilexetil. MRI indicated that LVMI decreased from 111.3 ± 31.3 g/m2 to 102.6 ± 32.1 g/m2 (P = 0.0484) and echocardiography that LVMI decreased from 123.9 ± 31.1 g/m2 to 115.8 ± 31.4 g/m2 (P = 0.0316). Total systemic vascular resistance decreased significantly during treatment with candesartan cilexetil in both MRI and echocardiography assessment, from 1847.2 ± 636.3 dynes·s·cm–5 to 1540.4 ± 432.0 dynes·s·cm–5 (P = 0.0034) on MRI and from 1820.4 ± 318.8 dynes·s·cm–5 to 1659.0 ± 317.7 dynes·s·cm–5 (P = 0.0060) on echocardiography. These findings suggest that candesartan cilexetil 2–8 mg/day orally for 8–12 weeks is beneficial in the regression of cardiac hypertrophy in patients with essential hypertension.     

Angiotensin II type 1 receptor blockers prevent aortic arterial stiffness in elderly patients with hypertension

Backgrounds and aims: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of ARBs in aged patients with essential hypertension are not entirely investigated.

Methods: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension.

Results: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared to patients without essential hypertension. In correlation analysis, PWV was associated positively with age, hypertension duration, and carotid atherosclerosis. However, there was no relationship between PWV and gender in aged patients with essential hypertension. In a perspective study, 6–12 months administration of ARBs (losartan, 50 mg/day; telmisartan, 40 mg/day; valsartan 80 mg/day; irbesartan, 150 mg/day) remarkably reduced PWV in aged patients with essential hypertension. Regression analyses of multiple factors indicated that the effects of ARBs on arterial stiffness were not associated with the reduction of blood pressure.

Conclusion: ARB treatment is a negative risk factor of arterial stiffness in aged patients with essential hypertension.     

Olmesartan, a novel angiotensin II type 1 receptor antagonist, reduces severity of atherosclerosis in apolipoprotein E deficient mice associated with reducing superoxide production

Background and aim

Oxidative stress may play an important role in the development of atherosclerosis. Some angiotensin II type 1 (AT₁) receptor antagonists have the capacity of reducing oxidative stress in addition to the hemodynamic actions. Accordingly, we assessed the hypothesis that olmesartan, a novel AT₁ receptor antagonist, reduced the severity of atherosclerosis in apolipoprotein (apo) E-deficient mice associated with reducing oxidative stress.

Methods and results

Atherosclerosis was induced in apo E-deficient mice fed a high fat diet. Mice were intraperitoneally treated with an injection of olmesartan (1 mg/kg/day) daily over 8 weeks, and were compared with the untreated controls. Blood pressure was not changed significantly by the olmesartan treatment. Fatty streak plaque developed in apo E-deficient mice, and was suppressed in mice that received olmesartan. In addition, olmesartan reduced not only superoxide production but the overload of oxidative stress in aortic walls. There were no significant differences in serum lipid levels between olmesartan-treated and -untreated groups. In vitro study showed that both olmesartan and its active metabolite RNH-6270, an enantiomer of olmesartan, suppressed interferon-γ, macrophage inflammatory protein-2, and thioredoxin (a marker of oxidative stress) concentrations in cultured cells.

Conclusion

Olmesartan may suppress atherosclerosis via reducing not only superoxide production but also the overload of oxidative stress in this animal model.     

Accelerated reversal of carbon tetrachloride-induced cirrhosis in rats by the endothelin receptor antagonist TAK-044

BACKGROUND: A multifunctional mediator, endothelin (ET)-1 is implicated in the pathophysiology of liver cirrhosis. Carbon tetrachloride (CCl4)-induced cirrhosis in rats resolves upon termination of CCl4 treatment. We determined the hepatic ET-1 system during such reversal and assessed whether ET-1 receptor antagonism enhances this process. METHODS: Cirrhosis was induced in rats by CCl4 treatment for 8 weeks. Treatment with an ETA/ETB antagonist TAK-044 (10 mg/kg per day) was then started and determinations were made at 1, 2 and 4 weeks. RESULTS: After termination of CCl4 treatment, accelerated normalization of liver architecture and portal hypertension occurred in TAK-044-treated rats compared with saline-treated rats. The increased hepatic hydroxyproline concentration and collagen I mRNA expression also declined to greater extents in the TAK-044-treated group. Higher collagenase activity in cirrhosis decreased in saline-treated rats, but did not reach basal values. In TAK-044-treated rats, collagenase activity tended to increase at weeks 2 and 4. Increased ET-1 concentration and ETA receptor density declined to normal values in both groups. In contrast, increased ETB receptor density did not change in saline-treated rats, but decreased to control values in TAK-044-treated rats. CONCLUSIONS: Our results emphasize the role of ET-1 in chronic liver disease and strongly indicate the potential for ET-1 receptor antagonists in its treatment.