Comparison of the effects of three angiotensin II receptor type 1 blockers on metabolic parameters in hypertensive patients with type 2 diabetes mellitus

ObjectiveIn a previous study involving 18 hypertensive patients with type 2 diabetes mellitus, we found that replacement of valsartan and candesartan by telmisartan significantly improved insulin sensitivity and significantly increased serum adiponectin levels in the patients. We investigated the effects of 3 angiotensin II type 1 receptor blockers (ARBs)—telmisartan, candesartan, and valsartan—on metabolic parameters in hypertensive patients with type 2 diabetes.MethodsA total of 308 hypertensive patients with diabetes were enrolled in our multicentre, randomized, open-label study. The patients received 40 mg telmisartan, 8 mg candesartan, or 80 mg valsartan for 3 months, and the data of 227 patients (telmisartan: n = 74, candesartan: n = 79, and valsartan: n = 74) were analysed.ResultsThe systolic and diastolic blood pressures significantly decreased in all the groups at the end of the study; the decrease was comparable among the 3 groups. The changes in fasting plasma glucose, fasting insulin, glycated haemoglobin (HbA1c), total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, adiponectin, free fatty acids, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor-1 (PAI-1) were comparable between the 3 groups. Telmisartan and candesartan administration tended to lower urinary albumin excretion.ConclusionsLow dose telmisartan had a neutral effect on metabolic dysfunction in hypertensive patients with type 2 diabetes; the effect produced by 40 mg telmisartan was comparable with that of 8 mg candesartan and 80 mg valsartan. Failure to detect metabolic differences among the various ARB treatments could have been due to the low statistical power of the study design.     

血管紧张素Ⅱ受体拮抗剂干预高血压患者尿酸代谢的对比研究

目的观察血管紧张素Ⅱ受体拮抗剂（ARB）氯沙坦与伊贝沙坦治疗对伴高尿酸血症的原发性高血压患者血清尿酸水平的影响并评价其降压疗效。方法采用多中心、随机、双盲、平行对照设计。伴高尿酸血症（血清尿酸浓度男性≥390μmo]／L,女性≥310μmo]／L）的1～2级原发性高血压患者,经2周安慰剂洗脱期后,随机分入氯沙坦组（50mg／d）或伊贝沙坦组（150mg／d）,治疗4周,如血压得到控制[收缩压〈140mmHg（1mmHg=0．133kPa）和舒张压〈90mmHg],继续原剂量治疗4周;如血压未得到控制[收缩压≥140mmHg和（或）舒张压≥90mmHg],将上述药物剂量加倍,继续治疗4周,观察血清尿酸浓度及血压的变化。结果随机入选351例患者,325例完成试验,氯沙坦组162例,伊贝沙坦组163例。与治疗前比较,氯沙坦组治疗4周末、8周末血清尿酸浓度明显降低（P〈0．0001）,伊贝沙坦组则无明显降低（P〉0．05）;两组之间比较,治疗4周、8周血清尿酸浓度氯沙坦组明显低于伊贝沙坦组（P〈0．0001）。与治疗前比较,两组治疗4周、8周末收缩压和舒张压均有明显下降（P〈0．0001）;两组之间比较,治疗4周、8周末收缩压和舒张压差异无统计学意义（P〉0．05）。结论氯沙坦治疗能显著降低伴高尿酸血症的原发性高血压患者的血清尿酸水平,伊贝沙坦无明显降低血清尿酸作用;两种ARB均能有效控制血压。因此,氯沙坦是治疗伴高尿酸血症的轻中度高血压患者的理想选择。     

Adverse effects of angiotensin II type 1 receptor blockers

Angiotensin II type 1 receptor blockers belong to a novel class of cardiovascular agents that is characterized by excellent tolerance. The overall rate of their side effects is similar to that of placebo. Specific nonproductive cough is much less common during treatment with angiotensin II blockers compared with angiotensin converting enzyme inhibitors. Nevertheless serious side effects very rarely occur with angiotensin II blockers and include cough, angioneurotic edema, anemia, liver damage, renal failure, aggravation of angina and migraine. The data of current literature concerning adverse effects of angiotensin II in different clinical situations are extensively reviewed. Angiotensin II type 1 receptor blockers are not considered to be safe in pregnancy, bilateral renal artery stenosis and severe renal or hepatic impairment.     

The role of angiotensin II type 1 receptor blockers in the prevention and management of diabetes mellitus

Angiotensin II Receptor blockers (ARBs) are an important addition to the current range of medications available for treating a wide spectrum of diseases including cardiovascular diseases. Coronary heart disease (CHD) is the most common cause of death in the United Kingdom and worldwide. More importantly, the presence of the metabolic syndrome and the likelihood of diabetes mellitus taking on epidemic proportions in the years to come all threaten to maintain the mortality rate due to CHD. This review article focuses on the clinical studies that have helped define the trends in the usage of these agents in the prevention and treatment of diabetes mellitus and its complications and also explores possible mechanisms of action and future developments.     

Effect of telmisartan-amlodipine combination at different doses on urinary albumin excretion in hypertensive diabetic patients with microalbuminuria

BACKGROUND: Aim of this study was to evaluate the effect of the telmisartan-amlodipine combination at different doses on urinary albumin excretion rate (UAER) in hypertensive diabetic patients with microalbuminuria. METHODS: After a 2-week placebo period, 300 hypertensive patients with type 2 diabetes and microalbuminuria were treated with the 40 mg of telmisartan and 2.5 mg of amlodipine combination. After 4 weeks 210 patients whose blood pressure (BP) was not controlled (BP >130/80 mm Hg) were randomized to two-dose titration regimens, one based on increasing doses of telmisartan (up to 160 mg daily) and fixed 2.5-mg dose of amlodipine, the other based on increasing doses of amlodipine (up to 10 mg daily) and fixed 40-mg dose of telmisartan. After 12 weeks the nonresponder patients were given transdermic clonidine (0.1mg/d). After 16 weeks the patients yet not controlled were discontinued, the others were followed for 48 weeks. Office BP, UAER, creatinine clearance, plasma potassium, fasting glycemia, and glycosylated hemoglobin were assessed at the end of the telmisartan (40 mg)/amlodipine (2.5 mg) treatment period and after 48 weeks of treatment. RESULTS: Similar decrease in systolic/diastolic BP values were obtained with both regimens (-24/-21, -23/-21, and -24/-21 mm Hg, all P < .001 v baseline, with increasing telmisartan; -25/-22, -25/-21, and -25/-22 mm Hg, all P < .001 v baseline with increasing amlodipine). Reductions of UAER were 47.5% (P < .01), 65.3% (P < .001), and 77% (P < .0001) for telmisartan 80, 120, and 160 mg/amlodipine 2.5 mg daily, respectively, whereas reductions of UAER were 34% (P < .03), 37% (P < .03), and 33% (P < .03) for amlodipine 5, 7.5, and 10 mg/telmisartan 40 mg daily, respectively, The difference between the two regimens was statistically significant (P < .05, P < .01, and P < .001, respectively). CONCLUSIONS: These findings indicate that, at comparable levels of BP reduction, UAE decreased more in subjects treated with escalating doses of telmisartan.     

Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients

BACKGROUND: The aim of this study is to compare the long-term effect of amlodipine and fosinopril in monotherapy or in combination on urinary albumin excretion (UAE) in hypertensive diabetic patients. METHODS: We selected 453 hypertensive patients with type 2 diabetes and microalbuminuria and randomized them to amlodipine (5 to 15 mg/day), fosinopril (10 to 30 mg/day), or amlodipine plus fosinopril (5/10 to 15/30 mg/day) for a 3-month titration period. The nonresponder patients or those complaining of side effects during the titration period were discontinued (n = 144); the remaining 309 patients were enrolled in the trial and treated with the same therapy for 4 years. Every 6 months, blood pressure (BP), heart rate (HR), UAE, creatinine clearance, and glycosylated hemoglobin (HbA1c) were evaluated. RESULTS: The combination therapy was more effective in reducing BP than either drug alone at any time of the study without affecting glucose homeostasis. All three treatments provided a significant decrease in UAE during the 48-month study period. However, this effect was more pronounced and became evident earlier with fosinopril than with amlodipine monotherapy (after 3 v 18 months of therapy). In addition, the combination therapy provided a greater antialbuminuric effect than the single drugs. This could be due to the greater antihypertensive effects, although other drug-specific effects cannot be excluded. The cardiovascular outcomes were similar in the amlodipine and in the fosinopril group, but they were lower in the combination group. CONCLUSIONS: These results strengthen the rationale to use a calcium-antagonist/angiotensin converting enzyme inhibitor combination in the treatment of hypertensive patients with type 2 diabetes.     

Platelet aggregability in patients with hypertension treated with angiotensin II type 1 receptor blockers

AIM: Cardiovascular events associated with hypertension often involve thrombosis. Increased platelet activity is one of the risk factors of cardiovascular diseases. Antithrombotic properties of antihypertensive agents are not fully characterized. Angiotensin II type 1 receptor blockers (ARBs) are widely used for the treatment of hypertension. Some ARBs can provoke antiaggregatory effects on platelets in vitro. Whether ARBs can inhibit platelet aggregation was tested in hypertensive patients in vivo. METHODS: Platelet aggregation was assessed by the highly sensitive particle counting method using laser-light scattering. RESULTS: Large platelet aggregation induced by adenosine diphosphate (ADP, 3 microM) was 2.6+/-0.4 (x10(7)) (SE) in hypertensive patients treated with losartan (72+/-3 years old, n=10) while it was 3.9+/-0.6 in hypertensive patients treated with candesartan (70+/-5 years old, n=6; p=0.056). Large platelet aggregation induced by thromboxane A2 receptor agonist, U46619 (10 microM), was 2.8+/-0.5 (x10(7)) in hypertensive patients treated with losartan while it was 5.1+/-0.9 in hypertensive patients treated with candesartan (p=0.033). Clinical characteristics including the control of blood pressure did not differ between the two groups (losartan 136+/-5/73+/-3 mmHg vs. candesartan 135+/-4/76+/-5). CONCLUSION: Thus, losartan may have the possibility to inhibit platelet activation in patients with hypertension independent of blood pressure reduction. Antiaggregatory properties may be independent of angiotensin II type 1 receptor or of antihypertensive actions. The favorable effects of losartan on reduction of adverse cardiovascular events among hypertensive patients may be at least partly mediated by inhibition of platelet activation.     

Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients

OBJECTIVES: We investigated the vascular effects of candesartan in hypertensive patients. BACKGROUND: The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The plausible mechanisms are that angiotensin II promotes superoxide anion generation, endothelial dysfunction, inflammation, and impaired fibrinolysis. The effects of candesartan on these conditions have not been clearly observed. METHODS: We administered placebo or candesartan 16 mg daily during two months to 45 patients with mild-to-moderate hypertension. This was a randomized, double-blind, placebo-controlled, crossover study in design. RESULTS: Candesartan did not significantly change lipoprotein levels. However, compared with placebo, candesartan significantly reduced plasma levels of malondialdehyde from 1.50 +/- 0.07 to 1.29 +/- 0.09 microM (p = 0.009); improved the percent flow-mediated dilator response to hyperemia from 5.17 +/- 0.24 to 6.22 +/- 0.26% (p < 0.001); and, furthermore, reduced plasma levels of monocyte chemoattractant protein (MCP-1) from 213 +/- 8 to 190 +/- 7 pg/ml (p = 0.003), tumor necrosis factor-alpha from 2.93 to 2.22 pg/ml (p = 0.026), and plasminogen activator inhibitor type 1 from 74 +/- 4 to 53 +/- 4 ng/ml (p < 0.001) but not C-reactive protein (CRP), matrix metalloproteinase protein, and fibrinogen. There were no significant correlations between these changes and reduction of systolic blood pressure (BP) (-0.247 < or = r < or = 0.195) and between these changes and reduction of diastolic BP (-0.262 < or = r < or = 0.197). There were no significant correlations between markers of inflammation and flow-mediated dilation percent or reduction of oxidant stress (-0.119 < or = r < or = 0.127). Furthermore, we observed no significant correlations between CRP and MCP-1 levels (r = -0.162). CONCLUSIONS: Inhibition of the angiotensin II type 1 (AT1) receptor in hypertensive patients reverses endothelial dysfunction, measured as an improvement in flow-mediated dilation and fibrinolysis and reduction of oxidant stress and inflammatory cytokines, suggesting that AT1 receptor blocker therapy has antiatherogenic effects.     

老年高血压病合并冠心病、脑梗塞患者AT1R基因多态性的研究

目的 探讨血管紧张素Ⅱ-Ⅰ型受体（AT1R）基因A1166／C多态性与老年原发性高血压病的关系，并探讨原发性高血压病的发病机制。方法 应用聚合酶链式反应、限制性内切酶酶解（PCR－RFLP）的方法检测40例健康人和92例原发性高血压病患者（其中31例合并冠心病，37例合并脑梗塞患者）的AT1R基因型；生化技术测定血脂水平。结果 原发性高血压病组、合并冠心病组及合并脑梗塞组的C等位基因频率14．6％、14．5％和10．8％，分别显著高于正常对照组的3．7％（P＜0．05）；带有C等位基因的原发性高血压病患者无论是否合并冠心病、脑梗塞，其血浆LP（a)水平均增高。结论 提示AT1R基因可能是老年原发性高血压病的重要遗传因素，AT1R基因可能参与脂质的调节。     

Emerging role of angiotensin II type 1 receptor blockers for the treatment of endothelial dysfunction and vascular inflammation

BACKGROUND: Angiotensin II type 1 receptor blockers (AT1RBs) share the effect of attenuating angiotensin II actions with angiotensin-converting enzyme inhibitors (ACEIs) but differ in other respects. Notably, the impact of unopposed angiotensin type 2 receptor stimulation and the absence of augmentation of bradykinin through inhibition of the kininase pathway may lead to differences between the effects of AT1RBs and ACEIs. ACEIs have been shown to improve endothelial dysfunction in many clinical settings. OBJECTIVE: To review current evidence regarding the effects of AT1RBs on endothelial dysfunction in patients. METHODS: MEDLINE and Current Contents searches, augmented by careful analyses of the bibliographies in the identified papers, were used to identify studies assessing the effects of chronic, oral use of AT1RBs on endothelial function and related inflammatory markers in patients. Animal studies and human studies using single doses or intravenous infusions were excluded. RESULTS: Clinical studies are available pertaining to the elderly and patients with coronary artery disease, hypertension and diabetes. The effect on endothelial dysfunction induced by postprandial lipemia has also been assessed. In general, AT1RBs improve vasomotor endothelial dysfunction and some inflammatory markers, but a few studies comparing ACEIs directly with AT1RBs suggest that AT1RBs may be inferior. AT1RB activity on endothelial dysfunction in patients with type I diabetes has not been shown. CONCLUSIONS: AT1RBs are an important addition to the therapy of endothelial dysfunction and vascular inflammation in patients. Further research is necessary to determine which AT1RBs and which dosing regimens are optimal.     

Unique mode of binding between angiotensin II type 1 receptor and its blockers

ABSTRACT

BACKGROUND: We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT₁R) blockers], may be responsible for the molecular effects of AZL. METHODS: We examined the binding affinities of AZL and CAN to AT₁R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild-type (WT) and mutants AT₁R-transfected cells. RESULTS: The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10^-6M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10^-6M AZL and AZL-7H did not. In addition, 10^-6M CAN, but not 10^-6M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS: The interaction between 5-oxo-1,2,4-oxadiazole in AZL and Arg¹⁶⁷ in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg¹⁶⁷.     

The relationship between mean platelet volume with microalbuminuria and glycemic control in patients with type II diabetes mellitus

Microalbuminuria is the best predictor of diabetic nephropathy development in patients with type II diabetes mellitus (DM). It is also accepted as an indicator of diabetic microangiopathy. Increased activation of platelets has been suggested to be involved in the pathogenesis of vascular complications. In light of these findings, this study was designed to investigate the association of microalbuminuria — an indicator glycemic control and microangiopathy — with mean platelet volume (MPV). Subjects underwent laboratory analyses and their MPV, HbA1c, serum creatinine, fasting, and postprandial blood glucose levels and 24-hour urine albumin levels were recorded. All statistical analyses were performed using SPSS v13.0 for Windows XP. Mann–Whitney U-test, student's t-test, spearman correlation analysis, ROC analysis, categorical regression analysis, and chi-square test were used for statistical evaluations. The study included 354 patients with type II DM. The median MPV value of microalbuminuria-positive patients was 9 (8–9.5)?fl while MPV of patients without microalbuminuria was 8.5 (8–9.2)?fl and the difference was statistically significant (p?=?0.004). We determined positive correlation between MPV and 24-hour urine microalbuminuria (r?=?0.14, p?=?0.009). There were no significant differences between patients with HbA1c levels below and above 7% in terms of MPV (p?>?0.05). We determined no correlation between MPV and HbA1c levels (r?=??0.36, p?=?0.64). This study determined a significant positive relationship between microalbuminuria — a microvascular complication of diabetes — and MPV. No significant correlation was identified between poor glycemic control and MPV in diabetic patients. However, we are in the opinion that the association between poor glycemic control and MPV in type II diabetic patients should be investigated in prospective studies with larger samples.     

不同血管紧张素受体拮抗剂对老年高血压患者血小板活性的影响

目的：探讨氯沙坦、厄贝沙坦及缬沙坦3种血管紧张素受体拮抗剂（ARB）对老年高血压患者血小板活性的影响。方法：入选年龄＞65岁、长期服用 ARB 的老年高血压患者90例,根据用药情况分成氯沙坦、厄贝沙坦、缬沙坦3个治疗组。分别测定各组血小板聚集率（PAR）、血管紧张素Ⅱ（Ang Ⅱ）、环氧化酶-2（COX-2）、血栓素 B2（TXB2）水平。比较经不同 ARB 处理的内皮细胞中,由 Ang Ⅱ诱导产生的 COX-2 mRNA 及蛋白表达量、TXB2水平。结果：氯沙坦、厄贝沙坦及缬沙坦组3组的 PAR分别为12．62％±0．74％、10．70％±0．70％和17．17％±1．44％,P ＜0．001;COX-2分别为（81．04±14．19）、（75．00±11．14）、（145．10±26．52）U／L,P ＝0．012;TXB2为（1577．00±161．90）、（1324．00±121．40）、（2025．00±154．10）pg／ml,P ＝0．004。与氯沙坦组相比,厄贝沙坦、缬沙坦组 COX-2 mRNA 及蛋白表达、TXB2水平下降更为显著,P ＜0．01。结论：厄贝沙坦、缬沙坦通过抑制 COX-2／TXB2表达,能更有效地抑制老年高血压患者的血小板活性。     

Increased inflammatory biomarkers in hypertensive type 2 diabetic patients: improvement after angiotensin II type 1 receptor blockade

Diabetes and hypertension increasingly are recognized as pro-inflammatory conditions. We tested the hypothesis that in patients with hypertension and type 2 diabetes, blood pressure (BP) reduction with an angiotensin receptor blocker (ARB), valsartan, or with a beta blocker, atenolol, is associated with a decreased inflammatory response. Normotensive subjects and hypertensive patients with type 2 diabetes (40 to 70 years of age) participated in the study. Patients (n = 28) were randomized to double-blind treatment for 1 year with valsartan (80–160 mg) or atenolol (50–100 mg) daily, added to previous therapy. Age-matched controls (n = 12) were also studied. Serum levels of cytokines (IL-6, IL-18), chemokines (MCP-1), and adhesion molecules (sICAM, sE-selectin) were measured by enzyme-linked immunosorbent assay (ELISA) as indices of systemic and vascular inflammation, before and 1 year after treatment. BP was similarly reduced by valsartan and atenolol. Glycemic control and lipid profiles were comparable in the two groups and did not change significantly with antihypertensive therapy. Serum levels of all inflammatory markers were increased in patients before treatment (by two- to four-fold vs. controls, P < .05). IL-6, IL-18, sICAM, and MCP-1 levels were reduced by valsartan (three-fold, P < .05). Only IL-18 was reduced by atenolol compared with pretreatment levels (P < .05). These data indicate that proinflammatory mediators are significantly increased in hypertensive type 2 diabetic patients and that despite similar BP lowering by valsartan and atenolol and similar glucose levels in both treated groups, global inflammatory status was improved only in the valsartan group. Our findings suggest that antihypertensive treatment, particularly with an ARB, ameliorates inflammatory processes in diabetic hypertensive patients. Such effects, which are independent of BP and glycemic control, may contribute to cardiovascular protection.     

Vascular protection in diabetes: a pharmacological view of angiotensin II type 1 receptor blockers

Vascular protection is key to reducing the morbidity associated with diabetes. Angiotensin II is known to exert a variety of deleterious effects on the vasculature, and this is likely to be a major explanation of the protective benefits observed with blockade of the renin-angiotensin-aldosterone system (RAAS). Intriguingly, RAAS blockade also appears to reduce the onset of new diabetes, which points to a fundamental effect on metabolism. Recent developments have thrown new light onto the mechanism of these effects. The importance of unopposed stimulation of the angiotensin II type 2 (AT(2)) receptor in vascular protection is recognised, and recent studies have revealed that some angiotensin II type 1 (AT(1)) receptor blockers (ARBs) show partial peroxisome proliferator-activated receptor-gamma (PPARgamma) agonistic activity in vitro, an effect that is at least partly due to direct interaction with PPARgamma itself. There is a clear order of potency among the ARBs, with telmisartan the most potent and the only ARB to show an effect at physiologically achievable plasma concentrations. Adiponectin, an adipokine closely involved with glucose sensitisation, is also modulated by the relative activation of AT(1) and AT(2) receptors. Such effects would suggest that important benefits may result from the use of ARBs in clinical practice, although confirmation of the clinical relevance will depend upon the results of numerous ongoing studies.     

血管紧张素Ⅱ-1型受体的shRNA对自发性高血压大鼠血压影响的实验研究

目的观察以重组腺病毒为载体的血管紧张素Ⅱ-1型受体的shRNA（AdS—AT1R—shRNA）对自发性高血压大鼠（SHR）血压的影响及对组织血管紧张素Ⅱ-1型受体（AT1R）基因表达的影响。方法在293细胞内扩增已构建好的荧光蛋白标记的携带AT1R shRNA的重组腺病毒（AdS—AT1R—shRNA）,TCID50法测定重组腺病毒滴度。22只SHR随机分为2组,实验组（n=11）和高血压对照组（n=11）,另设11只Wistar—Kyoto（WKY）大鼠为正常血压对照组,实验组SHR经鼠尾静脉单次注射Ad5—AT1R—shRNA,Ad5—AT1R—shRNA经TCID50法测定感染性滴度为1．7×10^9TCID50／ml,高血压对照组和正常血压对照组经鼠尾静脉单次注射对照重组复制缺陷型腺病毒（Ad5—EGFP）,感染性滴度为7.9×10^9TCID50／ml。注射前及注射后每天定时监测血压及心率,于血压出现明显下降时处死部分动物,取出心脏、肝脏、肾脏、主动脉及肾上腺组织,在荧光显微镜下观察他们对Ad5—AT1R—shRNA的吸收情况,采用荧光定量PCR检测肝脏、肾脏及主动脉组织AT1R mRNA的表达情况。结果实验开始24h后,实验组收缩压[（163±7）mmHg,1mmHg=0．133kPa]出现明显下降,最大降压幅度达29mmHg,与SHR组[（182±8）mmHg]比较差异有统计学意义（P〈0．05）,此后降压作用可持续5天,最长可持续7天。SHR组和WKY组血压均未见明显下降,SHR组有的血压可见继续升高。3组动物的心率变化不明显,肾脏、心脏、肝脏、主动脉及肾上腺组织在荧光显微镜下可见大量荧光表达。实验组肾脏及主动脉AT1R的mRNA表达量（分别为0．086±0．014,0,051±0．023）明显低于SHR组（分别为0．362±0．042,0．463±0．045）,P〈0,01。结论AdS—AT1R—shRNA经静脉注射后可被许多重要脏器吸收,且对SHR的AT1R起到RNA干扰的作用,在mRNA水平抑制AT1R的基因表达。AdS—AT1R·shRNA通过阻抑AT1R生成对SHR起到明显且持久的降压作用。     

Genetic contribution to the acute effects of angiotensin II type 1 receptor blockade

OBJECTIVE: Clinical observations point towards heterogeneity in patients' responses to antihypertensive drugs. As our earlier work showed that angiotensin II (AngII) sensitivity is associated with the A1166C polymorphism of the AngII type 1 receptor (AT1R) gene, we conducted the present study in which the responses to acute AT1R blockade were evaluated. METHODS: After 7 days of low and high sodium diet, the hormonal as well as systemic and renal hemodynamic responses to acute AT1R blockade with EXP3174 (active metabolite of losartan) were studied in 15 AA and 14 CC essential hypertensive patients. By means of platelet-binding studies the baseline AT1R density (Bmax) and affinity (KD) was tested. RESULTS: During low and high salt diet, baseline Bmax and KD were comparable between both genotype groups. At baseline, during low salt diet, CC patients had significantly lower glomerular filtration rate and a trend towards lower effective renal plasma flow (ERPF) compared to AA patients. Blood pressure responses to EXP3174 during high salt were significantly blunted in CC patients compared to AA patients (mean arterial pressure: 1.8 versus 7.5%; P < 0.05). During low salt the increase in ERPF (12.9 versus 16.1%; P = 0.08), as well as the decrease in filtration fraction (9.0 versus 14.0%; P = 0.05) and renal vascular resistance (7.5 versus 15.1%; P = 0.06) were blunted in CC patients compared to AA patients. Humoral effects did not differ between the groups. CONCLUSION: This study shows that the systemic and renal hemodynamic responses to acute AT1R blockade are, at least in part, genetically determined.