Inhibition of renin–angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation

Recent evidence indicates that renin–angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis. It was reported that inhibition of RAS with angiotensin II type 1 receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs) is effective in prevention of atherosclerosis. Here, we investigated the effects of an ARB or/and an ACEI on atherosclerosis development and periadventitial inflammation in apolipoprotein E (ApoE)-deficient mice. RT-PCR revealed that major RAS components were expressed in periaortic tissue. Ang II infusion significantly increased accumulation of bone marrow derived cells into both neointima (p < 0.05) and periaortic tissue (p < 0.01). Male ApoE- deficient mice were treated with either vehicle, TA606A (10 mg/kg/day, ARB), imidapril (3 mg/kg/day, ACEI) or TA606A plus imidapril (TA606A 10 mg/kg/day + imidapril 3 mg/kg/day, ARB + ACEI) for 24 weeks starting at 12 weeks of age. ARB, ACEI, and ARB + ACEI significantly reduced atherosclerotic lesion formation in aorta compared with vehicle (p < 0.05), with reduced expression of monocyte chemoattractant protein-1 in periaortic tissues (p < 0.01). Neither blood pressure nor heart rate was changed by the treatments at these lower doses. Imidapril significantly reduced lipid deposition in atheroma and plasminogen activator inhibitor-1 expression in periadventitial tissue (p < 0.05, respectively). Imidapril and combination therapy significantly attenuated macrophage infiltration into the atherosclerotic plaque (p < 0.05, respectively). All treatments reduced macrophage accumulation in the periadventitial tissue 12 weeks after treatment (p < 0.05, respectively). These results suggest that inhibition of renin–angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation.     

Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan

The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.     

替米沙坦对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块的作用及机制

目的 探讨血管紧张素Ⅱ受体拮抗剂(angiotension receptor blocker,ARB)替米沙坦对载脂蛋白E基因敲除小鼠动脉粥样硬化斑块面积及过氧化物酶体增殖物激活受体-δ(peroxisome proliferators activated receptor δ,PPAR-δ)、白细胞介素-1β(interleukin-1β,IL-1β)、转化生长因子-β1(transforming growth factor-β1,TGF-β1)表达的影响.方法 载脂蛋白E基因敲除小鼠60只,适应性喂养7d后随机分为普通饲料组(对照组)、高脂饲料组、高脂饲料+替米沙坦组(替米沙坦组)、高脂饲料+氯沙坦组(氯沙坦组)各15只.喂养8周后,采用无创血压系统检测小鼠鼠尾血压;经颈动脉取血检测血清总胆固醇、三酰甘油;采用HE染色评估胸主动脉根部斑块面积,采用Western blot法检测胸主动脉PPAR-δ、nL-1β和TGF β1蛋白表达情况.结果 高脂饲料组、替米沙坦组、氯沙坦组小鼠总胆固醇((15.6±2.3)、(14.8±3.1)、(15.1±2.9)mmol/L)、三酰甘油((3.8±0.6)、(3.5±0.5)、(3.6±0.7)mmol/L)均明显高于对照组((5.9±0.3)、(1.8±0.1)mmol/L) (P＜0.01);替米沙坦组、氯沙坦组小鼠收缩压((108±21)、(110±19)mm Hg)低于对照组((119±16)mm Hg)和高脂饲料组((1 2±25)mm Hg)(P＜0.01);替米沙坦组和氯沙坦组小鼠收缩压比较差异无统计学意义(P＞0.05);4组小鼠主动脉血管紧张素Ⅱ水平差异无统计学意义(P＞0.05);高脂饲料组胸主动脉根部斑块面积((3.31±0.19)×105 μm2)、11-1β水平(2.15±0.32)明显高于对照组((1.39±0.11)×105 μm2,0.92±0.10)、替米沙坦组((2.12±0.16)×105 μm2,1.08±0.15)和氯沙坦组((2.73±0.13)×105 μm2,1.71±0.11)(P＜0.05或P＜0.01),TGF-β1水平(0.63±0.12)低于对照组(1.80±0.30)、替米沙坦组(1.78±0.25)和氯沙坦组(0.98±0.13)(P＜0.05或P＜0.01),替米沙坦组胸主动脉根部斑块面积、IL-1β水平低于氯沙坦组(P＜0.05),TGF-β1水平高于氯沙坦组(P＜0.05);高脂饲料组胸主动脉PPAR-δ水平(0.60±0.10)低于对照组(1.21±0.10)和替米沙坦组(1.42±0.30)(P＜0.01),与氯沙坦组(0.62±0.15)比较差异无统计学意义(P＞0.05),替米沙坦组高于氯沙坦组(P＜0.01).结论 替米沙坦可能部分通过激活PPAR-δ调控炎症因子IL-1β与抗炎因子TGF β1的分泌,抑制动脉粥样硬化的发生发展.     

超声生物显微镜评价高脂饮食促进载脂蛋白E基因敲除小鼠动脉粥样硬化

目的 探讨应用超声生物显微镜(UBM)评价高脂饮食下载脂蛋白E(ApoE)基因敲除小鼠动脉粥样硬化的价值.方法 将32只8周龄ApoE基因敲除小鼠分为两组,一组饲以高脂饲料为高脂组,另一组饲以常规饲料作为对照组.饲养8周和16周后,采用Vevo 770超声成像系统观察两组小鼠升主动脉内-中膜厚度(IMT)及动脉粥样硬化斑块面积,并与病理组织学结果和血脂水平进行比较.结果 UBM显示高脂组和对照组小鼠主动脉根部管壁均增厚,出现粥样硬化斑块,但高脂组IMT及斑块面积均较对照组小鼠高,差异具有统计学意义(P＜0.05).UBM所测IMT及斑块面积与病理结果相关性良好(r分别为0.81和0.70);高脂组小鼠血清甘油三酯(TC)及总胆固醇(TG)水平均较对照组升高(P＜0.05),UBM所测IMT随TC水平升高而增加,两者呈正相关(r=0.528).结论 高脂饮食可促进ApoE基敲除小鼠主动脉粥样硬化斑块形成,超声生物显微镜能作为无创性观测手段来评价活体小鼠的动脉粥样硬化改变.     

AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats.

The effects of systemic treatment with the AT1 receptor antagonist telmisartan on central effects of angiotensin II (Ang II), namely, increase in blood pressure, vasopressin release into the circulation, and drinking response, were investigated in conscious, normotensive rats. The central responses to i.c.v. Ang II (30 ng/kg) were measured at 0.5, 2, 4, and 24 h following acute i.v. or acute and chronic oral telmisartan application. At a dose of 10 mg/kg i.v., the drinking response to i.c.v. Ang II was completely blocked over 4 h, while the pressor response and the release of vasopressin in response to i.c.v. Ang II were blocked by 60 to 80%. The inhibition of the centrally mediated pressor and drinking response to Ang II was sustained over 24 h. The lower doses of telmisartan (0.3 and 1 mg/kg) significantly inhibited the Ang II-induced actions over 4 h. A consistent 24-h inhibition of the central responses to i.c.v. Ang II was obtained after acute and chronic oral treatment with 30 mg/kg telmisartan. Oral treatment with 1 and 3 mg/kg telmisartan produced a slight but inconsistent inhibition of the central actions of Ang II. Telmisartan concentrations measured in the cerebrospinal fluid following 8 days of consecutive daily oral treatment (1-30 mg/kg) ranged from 0.87 +/- 0.27 ng/ml (1 mg/kg/day) to 46.5 +/- 11.6 ng/ml (30 mg/kg/day). Our results demonstrate that, following peripheral administration, the AT1 receptor antagonist telmisartan can penetrate the blood-brain barrier in a dose- and time-dependent manner to inhibit centrally mediated effects of Ang II.     

New effects of telmisartan, an angiotensin 2 receptor blocker, in the treatment of arterial hypertension with metabolic disorders

The authors undertook comparative analysis of the effica,cy and safety of PPARv-activating angiotensin-2 receptor blocker telmisartan (40--80 mg/day) in 80 patients with arterial hypertension (AH) and metabolic disorders (MD). Holter monitoring revealed a more pronounced anti-hypertensive effect of telmisartan compared with enalapril in patients with AH, MD, and compromised renal function. Similarly, telmisartan exerted more apparent positive effect on lipid and carbohydrate metabolism and had renoprotective action in patients with nephrogenic AH (it decreased proteinuria, stabilized creatinine clearance and serum potassium level whereas enalapril caused further deterioration of these parameters). It is concluded that telmisratan is more effective and safer than enalapril in patients with AH and MD.     

Treatment of hypertension in individuals with the cardiometabolic syndrome: role of an angiotensin II receptor blocker,telmisartan

Arterial hypertension is a global public health problem owing to its high prevalence and association with increased risk for cerebral, cardiac and renal events. Hypertension frequently clusters with other cardiometabolic risk factors, such as dysglycemia, low levels of high-density lipoprotein cholesterol and high triglyceride levels. These, along with other factors such as central obesity, increased inflammation, endothelial dysfunction and thrombosis, are components of the metabolic syndrome. All guidelines recommend that the first-line therapy in metabolic syndrome should be based on lifestyle modification, consisting of diet and moderate exercise for at least 30 min/day. Concerning drug treatment of hypertension associated with other cardiometabolic risk factors, many results of head-to-head studies have demonstrated a reduction in new-onset Type 2 diabetes in hypertensive patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, when compared with conventional antihypertensive therapy. The explanations of the different actions of both these drugs include several mechanisms related to pancreatic insulin release and insulin sensitivity improvement. Another mechanism by which the inhibition of the renin–angiotensin system may improve insulin sensitivity is through the partial peroxisome proliferator-activated receptor-γ agonism of telmisartan. For that reason, telmisartan has been considered by some experts to be an antihypertensive agent that is particularly useful in the treatment of hypertension associated with cardiometabolic risk factors. The impact of the promising metabolic action exhibited by telmisartan on the outcome of hypertensive patients aggregating other cardiometabolic risk factors waits for adequately randomized and powered clinical trials.     

Treatment of hypertension in individuals with the cardiometabolic syndrome: role of an angiotensin II receptor blocker, telmisartan

Arterial hypertension is a global public health problem owing to its high prevalence and association with increased risk for cerebral, cardiac and renal events. Hypertension frequently clusters with other cardiometabolic risk factors, such as dysglycemia, low levels of high-density lipoprotein cholesterol and high triglyceride levels. These, along with other factors such as central obesity, increased inflammation, endothelial dysfunction and thrombosis, are components of the metabolic syndrome. All guidelines recommend that the first-line therapy in metabolic syndrome should be based on lifestyle modification, consisting of diet and moderate exercise for at least 30 min/day. Concerning drug treatment of hypertension associated with other cardiometabolic risk factors, many results of head-to-head studies have demonstrated a reduction in new-onset Type 2 diabetes in hypertensive patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, when compared with conventional antihypertensive therapy. The explanations of the different actions of both these drugs include several mechanisms related to pancreatic insulin release and insulin sensitivity improvement. Another mechanism by which the inhibition of the renin-angiotensin system may improve insulin sensitivity is through the partial peroxisome proliferator-activated receptor-gamma agonism of telmisartan. For that reason, telmisartan has been considered by some experts to be an antihypertensive agent that is particularly useful in the treatment of hypertension associated with cardiometabolic risk factors. The impact of the promising metabolic action exhibited by telmisartan on the outcome of hypertensive patients aggregating other cardiometabolic risk factors waits for adequately randomized and powered clinical trials.     

Pterostilbene,a novel natural plant conduct,inhibits high fat-induced atherosclerosis inflammation via NF-κB signaling pathway in Toll-like receptor 5 (TLR5) deficient mice

Atherosclerosis is a specific form of an artery wall thickens, a syndrome affecting arterial blood vessels due to a chronic inflammatory response in the walls of arteries, which is promoted by fat accumulation. Toll-like receptors (TLRs) play prominent roles in inflammatory responses. And TLR5 is overexpressed in several diseases. Here in our study, we investigated the effect of TLR5 in high fat-induced atherosclerosis via NF-κB signaling pathway modulating pro-inflammatory cytokines releasing. Our results found that high fat induced atherosclerosis in wild type mice with fat accumulation and inflammatory response through NF-κB activation. Contrastly, TLR5 knockout mice displayed lower fat accumulation and ameliorated inflammation after high fat feeding with NF-κB inactivation. In addition, pterostilbene, as a natural dimethyl ether derivative of resveratrol mainly from blueberries, has diverse pharmacological activities, especially anti-inflammation. Our study also found that pterostilbene displayed inhibited role in suppressing inflammatory response through inactivating NF-κB signaling pathway regulated by TLR5 down-regulation in high fat-induced mice. Moreover, in vitro experiments of vascular smooth muscle cells (VSMCs) challenged with LPS or TNF-α, further indicated that NF-κB was involved in atherosclerosis progression, leading to high secretion of pro-inflammatory cytokines. However, VSMCs from TLR5 deficient mice inhibited phosphorylated levels of NF-κB signalilng pathway, finally resulting in down-regulation of inflammatory cytokines. Notably, pterostilbene also displayed suppressed role in inflammatory response via NF-κB inactivity in LPS or TNF-α-induced VSMCs by decreasing TLR5 expression. The results above indicated a novel therapeutic strategy of pterostilbene to protect against atherosclerosis via TLR5 regulation for clinic treatment in the future.     

In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of 12?I-Sar1-Ile?-AII to human angiotensin type 1 receptors with an IC?? of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC(50) value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC?? values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC?? values of 242.5, 191.6, >10,000, and >10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC?? value of 9.2 nmol; this effect was resistant to washout (IC?? value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC?? values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC?? value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pD'? value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.     

血管紧张素Ⅱ1型受体阻断剂预处理对小鼠动脉硬化后局灶性脑缺血再灌注脑损伤的影响

目的:探讨阻断血管紧张素Ⅱ1型受体对动脉粥样硬化小鼠脑缺血再灌注损伤的影响。方法:实验于2003-09/2004-12在南方医科大学中心实验室完成。选择载脂蛋白E基因敲除小鼠40只,随机分为对照组(n=20):高胆固醇食物喂养10周,替米沙坦预处理组(n=20):高胆固醇食物饲喂8周后替咪沙坦0.3mg/(kg·d)拌入食物中连续饲喂2周。喂养10周后同时建立缺血/再灌注脑损伤模型,缺血1h,再灌注23h。行相关指标的测定:用尾袖法测量血压;图像分析系统计算梗死面积百分比;计算两组动物死亡率;神经功能损害评分如下:0分为无神经功能损害体征,1分为右前爪肌力减弱,2分为躯体向左侧弯曲,3分为向左侧作旋转运动,4分为无自主运动;行脑组织含水量测定;在荧光显微镜下观察超氧化物阴离子的产生情况。结果:剔除实验结束前死亡动物,对照组死亡5只,替咪沙坦预处理组死亡4只。对照组15只和替咪沙坦处理组16只计入结果。①替咪沙坦预处理对动物血压的影响:与对照组比较,缺血前、后及再灌注后替咪沙坦预处理对动物血压无明显影响犤(101±3),(105±5)mmHg;(87±6),(88±3)mmHg;(93±5),(94±6)mmHg,P>0.05犦。②替咪沙坦预处理对梗死面积的影响:缺血/再灌注损伤后可见恒定的白色梗死灶,与对照组相比,替咪沙坦预处理组梗死面积减小,差异显著(P<0.05)。③替咪沙坦预处理对动物死亡率、神经功能缺陷评分和脑组织含水量的影响:与对照组相比,替咪沙坦预处理能降低动物死亡率及神经功能缺陷评分和脑含水量犤46.67%,31.13%;2.75±0.20,2.00±0.30;(83.29±0.45)%,(80.17±0.32)%,P<0.05犦。④替咪沙坦预处理对脑血流的影响:中脑动脉梗死后,梗死灶中心区脑血流均降至基线值20%以下,再灌注后预处理组脑血流高于对照组(P<0.05)。而梗死灶半暗区脑血流均降至基线值50%以下,梗死后30min至再灌注后,预处理组脑血流高于对照组(P<0.05)。⑤替咪沙坦预处理对氧应激的影响:梗死灶活性氧的产生增加,替咪沙坦预处理组活性氧的产生不明显。替咪沙坦预处理组还原型辅酶Ⅱ的活性较对照组明显减低犤(0.512±0.030),(0.782±0.032)mkat/g,P<0.05犦。结论:预先阻断血管紧张素Ⅱ1型受体可以缩小动脉粥样硬化小鼠脑缺血再灌注损伤的梗死面积,降低脑水肿和动物死亡率,改善神经功能缺失体征,抑制超氧化物阴离子的产生和还原型辅酶Ⅱ氧化酶活性增加,从而减轻了脑损害的程度。     

Ventricular and vascular remodelling effects of the angiotensin II receptor blocker telmisartan and/or the angiotensin-converting enzyme inhibitor ramipril in hypertensive patients

Angiotensin II induces inflammatory activation of vascular smooth muscle cells and can cause left ventricular hypertrophy (LVH). Telmisartan is an angiotensin II receptor blocker with demonstrated beneficial effects on cardiac and vascular structure and function in animal models. The angiotensin-converting enzyme inhibitor ramipril also reduces ventricular and vascular remodelling. The open-label study observed 75 treatment-naive, moderately or severely hypertensive (systolic blood pressure 160-190 mmHg, diastolic blood pressure 90-110 mmHg) patients (age range, 42-58 years) treated with once-daily telmisartan 40 mg force-titrated to 80 mg after 1 month (n=25), once-daily ramipril 2.5 mg force-titrated to 5 mg after 1 month (n=25), or once-daily telmisartan 40 mg plus ramipril 2.5 mg (n=25); the total duration of treatment was 6 months. At baseline, blood pressure, left ventricular mass index (LVMI), carotid intima-media thickness (IMT) and carotid cross-sectional intima-media area (CSA) were measured. Measurements were repeated 1, 3 and 6 months after initiation of treatment. After 6 months, comparable blood pressure reductions were achieved with the three treatments. Reductions in LVMI after 6 months' treatment were 11.4%, 9.9% and 15.6% with telmisartan, ramipril, and telmisartan plus ramipril, respectively. Respective reductions in IMT were 14.6%, 12.0% and 18.2%, and for CSA were 7.8%, 4.3% and 11.5%. In conclusion, treatment with telmisartan or ramipril for 6 months resulted in regression of LVH and vascular remodelling. When a combination of telmisartan and ramipril was administered, additional regression and remodelling occurred.     

小鼠动脉粥样硬化过程中血管壁的连接蛋白表达

目的：高脂饲料喂养ApoE-/-小鼠,构建动脉粥样硬化（AS）模型。观察在AS形成过程中,连接蛋白37（cx37）、cx40和cx43的表达情况。方法8周龄apoE-/-小鼠（AS组）、野生型小鼠（control组）各40只,同时予高脂饲料喂养,分别在高脂喂养的第0、4、8、12周采集标本。HE染色鉴定AS模型,免疫组化检测小鼠胸主动脉cx37、cx40和cx43的表达情况。结果两组小鼠血管SMC的cx37均呈高表达,且AS组的cx37表达呈上升趋势较control组明显（组间两两比较,0周、4周vs.8周、12周,P均＜0.05）。两组小鼠血管SMC的cx40呈稳定表达状态（P＞0.05）。两组小鼠血管SMC均无法检测到cx43的表达。结论 cx37可能作为连接蛋白的代表在小鼠AS形成过程中具有重要的意义,值得我们去深入研究。     

The telmisartan renoprotective study from incipient nephropathy to overt nephropathy--rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker, telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) Study

We planned the INNOVATION study to determine whether telmisartan, an angiotensin-2-receptor blocker, delays the progression of renal disease from incipient nephropathy to overt nephropathy in hypertensive or normotensive Japanese patients with type 2 diabetes mellitus. The INNOVATION study is a randomized, double-blind, placebo-controlled trial. Eligible patients must have incipient nephropathy (defined as a urinary albumin to creatinine ratio of 100-300 mg/g creatinine) and a serum creatinine concentration of < 1.5 mg/dl for men and < 1.3 mg/dl for women. Patients who need treatment with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors are excluded. Eligible patients are randomly assigned to three groups: telmisartan titrated to 40 mg; telmisartan titrated to 80 mg; or placebo. The primary endpoint is the time from baseline visit to first detection of overt nephropathy (defined by a urinary albumin to creatinine ratio that is > 300 mg/g creatinine and 30% higher than the baseline on at least two consecutive visits). A total of 1855 patients have been enrolled from 160 study centres. In 527 randomized patients (28.4% of the enrolled patients), mean (SD) urinary albumin to creatinine ratio and serum creatinine concentration at baseline were 173.3 (47.2) mg/g creatinine and 0.78 (0.19) mg/dl. Sixty-eight per cent of the patients had hypertension at baseline. Mean (SD) systolic and diastolic blood pressures at baseline were 137.1 (14.6) and 77.5 (10.3) mmHg. The INNOVATION study will determine whether telmisartan, an angiotensin II receptor blocker, provides clinical benefits in hypertensive or normotensive patients with diabetes mellitus and diabetic nephropathy.     

Effective treatment of hypertension by AT1 receptor antagonism: the past and future of telmisartan

Lowering blood pressure is the most effective treatment method to ensure a reduction in the total risk for cardiovascular morbidity and mortality. The renin–angiotensin system plays an important role in volume homeostasis and blood pressure regulation and is a target for several groups of pharmaceutical agents. Angiotensin II receptor blockers represent the newest class of antihypertensive compounds. They prevent the binding of angiotensin II to the subtype 1 receptor (AT₁), which is believed to mediate most of the physiological actions relevant to the regulation of blood pressure. Telmisartan, a widely used AT₁ receptor antagonist, is a highly selective compound with high potency, a long duration of action and a tolerability profile similar to placebo. Numerous randomized clinical trials and community-based studies have demonstrated that oral telmisartan and combinations of telmisartan with hydrochlorothiazide are at least as effective in lowering blood pressure as all other hypertensive medications. This has been demonstrated in different populations of adult patients with mild-to-moderate essential hypertension, including patients with coexisting Type 2 diabetes, metabolic syndrome or renal impairment. Several large-scale, long-term, clinical endpoint studies are in progress to assess the beneficial effects of telmisartan on hypertension-related end-organ damage in patients at high risk of renal, cardiac and vascular damage whose blood pressure is well controlled. The most recent data from clinical trials and latest research regarding telmisartan will be reviewed in this article.     

Cardiac troponin T content in heart and skeletal muscle and in blood samples from ApoE/LDL receptor double knockout mice

BACKGROUND: The isolated perfused mouse heart is a useful experimental model, and cardiac troponin T (cTnT) in coronary effluent may be a sensitive marker of myocardial damage. In recent years, the apolipoprotein E/low-density lipoprotein receptor double knockout (apoE/LDLr KO) mice have become valuable tools in atherosclerosis research. The aim of the study was to validate measurements of cTnT in heart, skeletal muscle, and serum of apoE/LDLr KO mice. METHODS: Wild-type C57BL/6J mice were fed with standard diet, and apoE/LDLr KO mice were fed an atherogenic diet. Blood was sampled from the jugular vein or the thoracic cavity. Heart and femoral skeletal muscle were sampled and homogenized. cTnT was measured with the third-generation cTnT assay (Troponin T STAT) on Elecsys 2010 immunoassay analyser (Roche Diagnostics). RESULTS: Median serum cTnT in samples from the thoracic cavity of C57BL/6J mice was about 20-90 times higher, and from ApoE/LDLr KO mice about 30 times higher than serum cTnT in samples from the external jugular vein. There was no difference in cTnT content (microg cTnT/g heart muscle) in hearts from C57BL/6J and apoE/LDLr KO mice. The median cTnT content in skeletal muscle was less than 0.1% of the cTnT content in heart muscle. CONCLUSION: There is no difference in cTnT content of heart muscle comparing C57BL/6J and ApoE/LDLr KO mice, which have larger hearts. Sampling from the thoracic cavity causes unacceptably high cTnT levels. Serum cTnT in samples from the jugular vein is only slightly elevated. Elevated baseline levels of cTnT in mice are not caused by troponin T from skeletal muscle.     

Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions that are, in part, driven by local AT1 receptor (AT1r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT1r blockade (losartan for 8 weeks) on AT1r and AT2r and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor kappaB (NFkappaB), 12-lipooxygenase, cyclooxygenase (COX)-1, COX-2, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (PAI)-1, renal T cell, and macrophage infiltration] as well as renal function and structure. The untreated group exhibited hypertension, deterioration of renal function and structure, reduced or unchanged plasma renin activity, aldosterone concentration, marked up-regulations of AT1r (250%), Ang II-expressing cell count (>20-fold), NAD(P)H oxidase subunits (gp91(phox,) p22(phox), and P47(phox); 20-40%), COX-2 (250%), 12-lipooxygenase (100%), MCP-1 (400%), and PAI-1 (>20-fold), activation of NFkappaB, and interstitial infiltrations of T cells and macrophages in the remnant kidneys. AT1r blockade attenuated the biochemical and histological abnormalities, prevented hypertension, and decelerated deterioration of renal function and structure. Thus, the study demonstrated a link between up-regulation of Ang II/AT1r system and oxidative stress, inflammation, hypertension, and progression of renal disease in rats with renal mass reduction.     

miR-29a对ApoE基因敲除小鼠动脉粥样硬化形成的作用及分子机制

目的探讨miR-29a对载脂蛋白(Apo)E基因敲除小鼠动脉粥样硬化(AS)形成的作用及分子机制。方法将实验动物分为5组,B6组C57BL/6J小鼠3只,正常饮食;AD组载脂蛋白E(ApoE)敲除小鼠3只,正常饮食;AG组ApoE敲除小鼠3只,高脂饮食;AP组ApoE敲除小鼠3只,尾静脉注射pAd-GFP腺病毒,高脂饮食;AM组ApoE敲除小鼠3只,尾静脉注射pAdmiR-29a病毒,高脂饮食。高脂饲喂ApoE基因缺陷小鼠快速形成AS模型,高分辨力超声检查miR-29a对脂质斑块形成的影响,HE染色检查动脉斑块形成情况,免疫组织化学检测miR-29a对斑块血管平滑肌细胞(VSMCs)增殖及锌指蛋白转录因子5(KLF5)表达的影响。结果 ApoE敲除小鼠经miR-29a转染可见低回声脂质斑块,miR-29a转染可以促进斑块组织内VSMCs的增殖,并上调KLF5的表达。结论 miR-29a促进了ApoE基因缺陷小鼠动脉斑块内VSMCs的增殖,其分子机制可能与上调增殖相关转录因子KLF5的表达有关。