Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.     

Antihypertensive Effects of Olmesartan Compared with Other Angiotensin Receptor Blockers

Objectives: Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. Data Sources: Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7, 2010). Review Methods: Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. Results: Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. Conclusion: Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan.     

血管紧张素Ⅱ受体拮抗药对肝纤维化患者血清学指标影响的Meta分析

目的:系统评价血管紧张素Ⅱ受体拮抗药(ARBs)对肝纤维化患者血清学指标的影响。方法:计算机检索PubMed、中国期刊全文数据库及万方数据库中关于ARBs治疗肝纤维化的临床随机对照试验(RCT),对符合纳入标准的临床研究进行评估与资料提取后,采用Rev Man 5.2统计软件进行Meta分析。结果:共纳入9项RCT,合计457例患者。Meta分析结果表明,ARBs可以显著降低肝纤维化患者血清玻璃酸(HA)[WMD=-66.31,95%CI(-102.80,-29.82),P=0.000]、层黏蛋白(LN)[WMD=-44.49,95%CI(-70.28,-18.69),P=0.000]、血清Ⅳ型胶原(CⅣ)[WMD=-36.40,95%CI(-61.84,-10.95),P=0.005]、血清Ⅲ型前胶原氨基端肽(pⅢp)[WMD=-41.29,95%CI(-74.57,-8.02),P=0.02]水平。结论:在常规治疗基础上,加服ARBs治疗肝纤维化,能够明显改善患者血清HA、LN、CⅣ及pⅢp等相关指标。由于纳入研究的质量不高,此结论有待更多高质量、大样本的RCT加以验证。     

Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC₅₀) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC₅₀ indicate that these ARBs might inhibit the AA metabolism in the liver.     

Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Prothrombotic Processes and Myocardial Infarction Risk

Acute ischemic events occur most frequently at dawn and in the early hours of the morning. The development of these severe clinical events exhibits a temporal relationship with changes in various hemodynamic, prothrombotic, and hormonal processes. The authors highlight not only these relationships but also the potential protective effect of increased bradykinin levels and the inhibition of different angiotensin II (AT-II) receptors (AT2, AT4) against unfavorable prothrombotic influences, which—based on studies to date—decreases the risk of acute cardiovascular events. Comparisons are presented between the different effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on factors that influence thrombus formation and myocardial infarction risk.     

ACE抑制剂与血管紧张素Ⅱ受体拮抗剂联用的作用（三）

为了方便广大执业药师进行继续教育学习，《中国执业药师》杂志特意为订阅本刊的执业药师开辟了“CE课堂”这个栏目，每期刊登与执业药师执业活动密切相关的继续教育的文章，每篇文章末尾将附上相应的测试题．以期刊答题的形式授予执业药师继续教育自修学分。请参与答题的执业药师在认真学习“CE课堂”的内容后。将答案寄回本刊编辑部。根据《执业药师继续教育管理暂行办法》的规定，考核合格者。将授予全国有效的执业药师继续教育自修学分（每题0．1加．5学分，全年最高记5学分）和学分证明。     

ACE抑制剂与血管紧张素II受体拮抗剂联用的作用（一）

为了方便广大执业药师进行继续教育学习。《中国执业药师》杂志特意为订阅本刊的执业药师开辟了“CE课堂”这个栏目，每期刊登与执业药师执业活动密切相关的继续教育的文章，每篇文章末尾将附上相应的测试题。以期刊答题的形式授予执业药师继续教育自修学分。请参与答题的执业药师在认真学习“CE课堂”的内容后，将答案寄回本刊编辑部。根据《执业药师继续教育管理暂行办法》的规定，考核合格者，将授予全国有效的执业药师继续教育自修学分（每题0．1～0．5学分，全年最高记5学分）和学分证明。 本期的自修课程为（（ACEI与血管紧张素II受体拮抗剂联用在心血管病中的作用》，全文分期连载，测试题将刊登在文章结尾处，请清楚回答后寄回本刊编辑部，合格者将授予继续教育自修学分。     

ACE抑制剂与血管紧张素Ⅱ受体拮抗剂联用的作用（二）

为了方便广大执业药师进行继续教育学习，《中国执业药师》杂志特意为订阅本刊的执业药师开辟了“CE课堂”这个栏目，每期刊登与执业药师执业活动密切相关的继续教育的文章，每篇文章末尾将附上相应的测试题，以期刊答题的形式授予执业药师继续教育自修学分。请参与答题的执业药师在认真学习“CE课堂”的内容后，将答案寄回本刊编辑部。根据《执业药师继续教育管理暂行办法》的规定，考核合格者，将授予全国有效的执业药师继续教育自修学分（每题0．1～0．5学分，全年最高记5学分）和学分证明。 本期的自修课程为（（ACEI与血管紧张素II受体拮抗剂联用在心血管病中的作用》，全文分期连载，测试题将刊登在文章结尾处，请清楚回答后寄回本刊编辑部，合格者将授予继续教育自修学分。     

ACE抑制剂和血管紧张肽Ⅱ受体阻滞剂门诊处方调查

目的:通过对医院门诊血管紧张素转换酶(ACE)抑制剂和血管紧张肽(AⅡ)受体阻滞剂的处方调查,以了解医生处方习惯和这两类药物的门诊应用情况。方法:回顾性调查华东医院2001-11～2002-01共3个月的门诊处方,包括ACE抑制剂和AⅡ受体阻滞剂的处方频度、药物类别、剂量、合并处方、患者的性别和年龄分布等情况。结果:3个月门诊处方量分别为18381、22186和20866张,其中ACE抑制剂的处方频度分列为4.2％、5.1％和4.7％,以福辛普利和苯那普利的处方频度最高,依那普利和赖诺普利的处方频度最低。患者平均年龄65.3±10.9岁,男性多于女性,89.9％的患者合并1种或以卜处方药物。AⅡ受体阻滞剂氯沙坦的处方频度分别为0.70％、0.84％和0.88％,患者平均年龄65.1±11.7岁。处方剂量多数在治疗指南和建议推荐的剂量范围的低限。22张处方在用ACE抑制剂的同时合并处方AⅡ受体阻滞剂。结论:门诊ACE抑制剂和AⅡ受体阻滞剂的处方应根据患者的耐受性和经济情况等加以选择,并按治疗指南或建议进行给药方案调整。     

急性心肌梗死患者血管紧张素转化酶抑制剂和血管紧张素受体阻滞剂的应用及影响因素

目的 了解天津市静海区急性心肌梗死(AMI)患者中血管紧张素转化酶抑制剂和血管紧张素受体阻滞剂(ACEI/ARB)的使用情况,并探讨其影响因素.方法 通过调查天津市静海区医院2001、2006、2011三个特定年份的研究病历,分析ACEI/ARB的使用情况,并采用二元lo-gistic回归方法 探讨其使用的影响因素.结果 共入选598例患者,其中中国指南Ⅰ类推荐组589例,指南Ⅱa类推荐组9例.2001年、2006年和2011年,指南Ⅰ类推荐患者ACEI/ARB使用率分别为69.86%、64.11%和69.97%(P>0.05),2001年、2006年和2011年指南Ⅱa类推荐患者为32.65%、33.33%和50.00%(P>0.05).ACEI/ARB使用率随时间推移呈小幅提高.在3个研究年份中,ACEIs使用率均显著高于ARBs.多因素分析显示,与对应组相比合并高血压(OR 2.20,95%CI 1.50~3.30)、心力衰竭(OR 1.70,95%CI 1.20~2.60)的患者更倾向于使用ACEI/ARB,相反,合并eGFR<60mL/(min·1.73m2)的患者较少使用ACEI/ARB(OR 0.30,95%CI 0.20~0.70).结论 约三分之一静海区急性心肌梗死Ⅰ类推荐患者住院期间未接受ACEI/ARB治疗,随时间推移呈小幅提高.     

Involvement of Uric Acid Transporters in Alteration of Serum Uric Acid Level by Angiotensin II Receptor Blockers

Purpose To examine the mechanisms of the alteration of serum uric acid level by angiotensin II receptor blockers (ARBs), the effects of ARBs on renal uric acid transporters, including OAT1, OAT3, OAT4, and MRP4, were evaluated. Materials and Methods Uptakes of uric acid by OAT1-expressing Flp293 cells, by Xenopus oocytes expressing OAT3 or OAT4, and by membrane vesicles from Sf9 cells expressing MRP4 were evaluated in the presence or absence of ARBs. Results All ARBs inhibited uptake of uric acid or estrone-3-sulfate by OAT1, OAT3 and OAT4 in concentration dependent manners. Among them, the IC₅₀ values of valsartan, olmesartan and pratosartan for OAT3 were comparable to clinically observed unbound maximum plasma concentration of ARBs. Candesartan, losartan, and telmisartan inhibited ATP-dependent uptake of uric acid by MRP4 at 10 μM. The IC₅₀ value of losartan for MRP4 was comparable to the estimated kidney tissue concentration of losartan. No ARBs showed trans-stimulatory effects on the uptake of estrone-3-sulfate by OAT4. Conclusion Valsartan, olmesartan, and pratosartan could inhibit the OAT3-mediated uric acid secretion in clinical situations. Furthermore losartan could inhibit ATP-dependent uric acid secretion by MRP4. These effects may explain partially the alteration of serum uric acid level by ARBs.     

Neointimal Hyperplasia Inhibition Effect of Angiotensin II Type 1 Receptor Blockers in Patients after Coronary Stent Implantation

Background and Objective

It remains unclear whether angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can inhibit neointimal hyperplasia after stent implantation in patients with coronary artery disease. The aim of this meta-analysis was therefore to evaluate the benefits of ARBs in patients after coronary stent implantation based on the currently available randomized controlled trials.

Methods

We conducted a pooled analysis of randomized controlled trials to compare outcomes after stent implantation in patients administered ARBs with those not administered ARBs. We searched Ovid/MEDLINE, EMBASE, and the ISI web of knowledge using the terms ‘angiotensin receptor blocker,’ ‘renin angiotensin system inhibitor,’ ‘angiotensin receptor antagonist,’ ‘stent,’ ‘angiograph,’ ‘percutaneous coronary intervention (PCI),’ and ‘coronary artery disease.’ Published meta-analyses, review articles, and editorials were reviewed for potential studies of interest. The inclusion criteria were randomized controlled trials published in English, with a follow-up period of 6 months, comparing the outcomes after coronary stent implantation with and without the administration of any kind of ARB, reporting at least one outcome of interest (restenosis rate and late lumen loss). Data abstraction included study design, patient characteristics, follow-up period, type of ARB, type of stent, restenosis rate, and late lumen loss. Fixed-effects models were used to calculate the pooled relative risk for the restenosis rate and the standardized mean difference for late lumen loss.

Results

Five studies were included, with a total number of 624 patients. Seventy-five of 314 patients in the ARB group were diagnosed with in-stent restenosis at the 6-month follow-up, compared with 87 of 310 patients in the control group (relative risk 0.85; 95% CI 0.65, 1.11; p = 0.23). Consistent with this, there was no significant difference in late lumen loss between the two groups (0.04 mm; 95% CI ?0.15, 0.23; p = 0.66).

Conclusion

There is no evident benefit with the use of an ARB in terms of inhibition of neointimal hyperplasia in patients after coronary stent implantation.     

Differences in the Clinical Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Critical Review of the Evidence

The renin–angiotensin–aldosterone system plays a major role in the pathophysiology of hypertension and closely related cardio- and cerebrovascular events. Although both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are equally important in the treatment of hypertension, according to the results of recent years, there might be substantial differences in their cardiovascular protective effects, and these differences might be explained by our increasing knowledge of their non-overlapping mechanisms of action. The number of studies investigating how ACE inhibitors and ARB agents differ will certainly be increasing in the future. ACE inhibitors are the safe therapeutic opportunity for hypertensive patients at high risk, with a cardiological comorbidity.     

Comparison of Hyperkalemic Risk in Hospitalized Patients Treated with Different Angiotensin Receptor Blockers

Background and Aim

Clinical use of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) is associated with hyperkalemia as an adverse drug reaction. Although it has significant clinical implications, the incidence and relative risks of hyperkalemia with various ARBs have not yet been fully evaluated. The purpose of this study was to determine the risk of hyperkalemic events in hospitalized patients treated with different ARBs and to compare the risk among them.

Methods

We constructed a retrospective cohort composed of hospitalized adult patients who took ARBs in a single tertiary teaching hospital between April 2004 and March 2010. We estimated the incidence of hyperkalemia (serum potassium level >5.5 mEq/L) with various ARBs, and then compared the risk between them using a multivariate Cox proportional hazard model based on age, sex, Charlson co-morbidity score, baseline serum potassium, underlying diseases, and concomitant drugs.

Results

We identified 6992 evaluable intervals from 5449 patients treated with one of the seven ARBs during hospitalization over the 71-month study period with 2521.6 patient-months. We found 381 hyperkalemic events (5.4%) during the study period and an overall event rate of 15.1/100 patient-months. Moderate to fatal hyperkalemia was relatively rare (>6.0 mEq/L, 2.1% [moderate]; >6.5 mEq/L, 0.9% [severe]; >7.0 mEq/L, 0.3% [fatal]). After adjustment for covariates, telmisartan showed a lower risk of hyperkalemia (hazard ratio 0.67; 95% confidence interval 0.51, 0.89) compared with all other ARBs.

Conclusion

The risk of hyperkalemic events in hospitalized patients treated with different ARBs was defined. Telmisartan showed a relatively lower hyperkalemic risk profile in hospitalized patients compared with other ARBs.     

Angiotensin II Receptor Antagonists Alone and Combined with Hydrochlorothiazide

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.     

4种血管紧张素Ⅱ受体拮抗药治疗轻中度高血压的成本-效果分析

目的:评价4种血管紧张素Ⅱ受体拮抗药治疗轻中度高血压的成本-效果。方法:104例轻、中度高血压患者分为4组,分别应用替米沙坦、氯沙坦钾、厄贝沙坦、缬沙坦治疗,8wk后比较临床效果并进行成本-效果分析。结果:4种用药方案在疗效比较上差异无统计学意义(P>0·05),成本分别为684·00、760·80、659·20、720·80元,成本-效果比分别为7·74、9·51、7·91、8·07。结论:替米沙坦从药物经济学的角度分析为治疗轻中度高血压的较优药物。     

Investigation Planning and Bioequivalence evaluation of Angiotensin II Receptor Antagonists

Pharmaceutical Chemistry Journal - Results of a retrospective analysis of bioequivalence studies of generic angiotensin II receptor antagonists are presented. Losartan, valsartan, and telmisartan...     

Prodrugs to Improve the Oral Bioavailability of a Diacidic Nonpeptide Angiotensin II Antagonist

DMP 811 is a diacidic angiotensin II antagonist. It has relatively low oral bioavailability in rats. A prodrug approach to improving oral bioavailability was tested. Five esters were synthesized and their stability in rat plasma in vitro was determined. The hydrolysis rates of these five esters ranged from almost immediate to negligible. A simple n-propyl ester was hydrolyzed very slowly (< 10% in 24 hr) in rat plasma in vitro, and after oral dosing in rats plasma prodrug concentrations were much greater than DMP 811 concentrations. A pivaloyloxymethyl ester (1) was hydrolyzed relatively rapidly in rat plasma in vitro. Prodrug 1 was rapidly hydrolyzed by the intestine in vitro, and the intestinal permeation of DMP 811 was increased. DMP 811 oral bioavailability was 47% in rats dosed with 10 mg/kg 1, compared to 11% for rats dosed with 10 mg/kg DMP 811. However, DMP 811 bioavailability was only 27% after a 2 mg/kg dose of 1. In vitro plasma hydrolysis of 1 was highly species-dependent, with a half-life of 13 hr in human plasma but only 1 min in rat plasma. The prodrug approach has potential for improving the oral bioavailability of DMP 811, but selection of the optimal prodrug must be done in humans or in a species, such as dogs, with hydrolysis characteristics closer to humans.     

Comparative Cardiovascular Effects of the Angiotensin II Type 1 Receptor Antagonists ZD 7155 and Losartan in the Rat

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats. The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng—12.8 μg kg^?1 min^?1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 μmol kg^?1 (0.51 mg kg^?1) and losartan in bolus doses of 2.165 and 6.495 μmol kg^?1 (1.0 and 3.0 mg kg^?1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg^?1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 μmol kg^?1 bolus dose and angiotensin II was given at 240 ng kg^?1 (in a 10?min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 μmol kg^?1) and losartan (6.495 μmol kg^?1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect.