直接肾素抑制剂阿利吉仑治疗高血压病的研究进展

阿利吉仑是第一个用于临床的口服直接肾素抑制剂。临床试验表明,其降压效果与氯沙坦、厄贝沙坦、赖诺普利、雷米普利等一线降压药相当,与血管紧张素转化酶抑制药（ACEI）、血管紧张素Ⅱ受体拮抗药（ARB）、钙通道阻滞药（CCB）或利尿剂等联合使用时降压作用增强。另外,阿利吉仑具有一定的心脏保护作用,且安全性和耐受性良好。本文简要综述了阿利吉仑在治疗高血压病方面的研究进展。     

Aliskiren,the first in a new class of direct renin inhibitors for hypertension: present and future perspectives

Aliskiren, the direct renin inhibitor, is the first new class of drug available in 13 years for the treatment of hypertension. Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile. Aliskiren possesses possible synergistic potential when combined with a thiazide diuretic, ACE inhibitor, angiotensin receptor blocker and calcium channel blocker both in terms of efficacy and tolerability. This review aims to define the role of aliskiren in the therapeutic management of hypertension.     

新型口服抗高血压药阿利克伦的临床药理学研究进展

肾素直接抑制剂阿利克伦是一种新型、安全、有效的口服抗高血压药物,并且具有肾脏保护、减少左心窒肥厚等作用,可以单用或者与ACE抑制剂(如雷米普利)、Aug Ⅱ受体阻滞剂(如缬沙坦)和噻嗪类利尿剂等降压药物联合使用,降压作用具有剂量依赖性,病人耐受性良好.     

Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit

1. Renin inhibitors may be more advantageous than either angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin-angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma. 2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two-kidney one-clip Goldblatt rabbit. 3. At doses of 2-2.5 mg/kg, i.v., EMD 58265 and 5-10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2-4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF. 4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII. 5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.     

肾素抑制剂阿利吉仑治疗高血压的研究进展

肾素抑制剂作用于肾素-血管紧张素系统初始环节,能够有效降低血压、保护靶器官.阿利吉仑是首个成功开发上市的口服肾素抑制剂,其在高血压治疗及靶器官保护方面前景光明.     

肾素抑制剂阿利克仑的药理与临床评价

阿利克仑是一种有效的肾素抑制剂,它比早期的肾素抑制剂口服吸收更好,而且半衰期很长,每日1次即可,是一种很有前途的新型降压药。长期数据还未公布。现对其药理作用、药动学、临床疗效及安全性等做一综述。     

肾素-血管紧张素-醛固酮系统抑制剂多靶点干预治疗高血压的研究进展

肾素-血管紧张素-醛固酮系统(RAAS)是参与高血压发病和维持不可或缺的环节;RAAS抑制剂治疗高血压被临床广泛应用,其中主要包括直接肾素抑制剂、血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂.它们作用于RAAS不同靶点,对RAAS抑制剂有效性的影响及其临床应用地位和意义一直被人们所关注,因此对三者各靶点作用特点的进行总结,以揭示RAAS抑制剂多靶点干预的重要性和意义.     

Protection against tacrolimus-induced cardiotoxicity in rats by olmesartan and aliskiren

Context: Tacrolimus (TAC), a calcineurin inhibitor, is commonly used as an immunosuppressive agent in organ transplantation, but its clinical use may be limited due to cardiotoxicity. Olmesartan (OLM; angiotensin receptor blocker) and aliskiren (ALK; renin inhibitor) may attenuate cardiotoxicity induced by TAC by inhibition of renin–angiotensin aldosterone system.

Objective: The aim of this study was to evaluate the effect of OLM and ALK on TAC-induced cardiotoxicity.

Materials and methods: Male Wistar albino rats weighing 200–250?g (10–12 weeks old) were used in this study. Animals were divided into four groups. Group 1 received normal saline, group 2 received TAC (2?mg/kg, intraperitoneally for 14?d), group 3 received OLM (2?mg/kg, p.o. for 28?d)?+?TAC and group 4 received ALK (50?mg/kg, p.o. for 28?d)?+?TAC. TAC-induced cardiotoxicity was assessed biochemically and histopathologically.

Results: Treatment with OLM or ALK decreased the TAC-induced changes in biochemical markers of cardiotoxicity such as serum aspartate transaminase, creatine kinase and lactate dehydrogenase. OLM or ALK also attenuated the effects of TAC on oxidant–antioxidant parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that OLM or ALK also attenuated TAC-induced cardiotoxicity.

Discussion and conclusion: These results suggest that OLM as well as ALK has protective effects against TAC-induced cardiotoxicity; implying that angiotensin receptor blocker or renin inhibitor, respectively, may counteract cardiotoxicity associated with immunosuppressant use.     

Aliskiren: beyond blood pressure reduction

Importance of the field: Hypertension is one of the most important risk factors and causes of cardiovascular disease (CVD). From some years, renin-angiotensin-aldosterone system (RAAS) inhibitors such angiotensin converting enzyme (ACE) and angiotensin receptor blockade (ARB) have been of interest, not only for better blood pressure (BP) control but also for their involvement in the mechanisms of various organ functions.

Areas covered in this review: The aim of this review is to focus on the effectiveness and safety of aliskiren beyond the treatment of hypertension.

What the reader will gain: Aliskiren, the first approved renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic non-peptide molecule that blocks angiotensin I generation. Because of its mechanism of action, aliskiren may offer the additional opportunity to inhibit progression of atherosclerosis at tissue level and the potential to be useful in a wide spectrum of conditions. However, we will discuss how it might become a reasonable therapeutic choice also in a broad number of clinical conditions, sharing an increased cardiovascular risk as stable coronary artery disease (CAD), microvascular and cardio-renal disease, diabetes, and peripheral arterial disease (PAD).

Take home message: Therapy of hypertension through a better blockade of RAAS may be the first step in also achieving interesting results in the complications that hypertension causes in several organs.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ENDOGENOUS ANGIOTENSIN II LEVELS AND THE MECHANISM OF ACTION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR TYPE 1 ANTAGONISTS

• 1 Modification of endogenous angiotensin II (AngII)-mediated processes by inhibitors of the angiotensin-converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT₁) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels.
• 2 Both ACE inhibitors and AT₁ receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT₁ receptor antagonists produce incomplete blockade of AT₁ receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist.
• 3 The effects of ACE inhibitors and AT₁ receptor antagonists on AngII levels show tissue specificity. Angiotensin II-mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT₁ receptor antagonists. The inhibition of AngII-mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT₁ receptor antagonists on blood pressure and other aspects of cardiovascular function and structure.
• 4 Combination of an ACE inhibitor with an AT₁ receptor antagonist prevents the rise in plasma AngII levels that occurs with AT₁ receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII-mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT₁ receptor antagonism results in superior clinical outcomes.

     

Angiotensin-converting enzyme inhibitor-related angioedema: how to deal with it

Angiotensin-converting enzyme inhibitor-related angioedema is a well documented condition, which seems to occur in up to 1% of treated patients. It represents a problem for both the clinician and the patient: for the clinician, the diagnosis may be difficult due to its peculiar clinical characteristics, whereas for the misdiagnosed patient the delay prolongs a potentially dangerous situation. If the drug is not discontinued, the attacks tend to become worse and even life-threatening. There are now evidences that increased levels of bradykinin have an important role in the pathophysiology of attacks and, moreover, there are genetic factors that render certain individuals susceptible to angiotensin-converting enzyme inhibitor-related angioedema. In this review, the authors analyse the pathogenetic mechanism, the clinical presentation, the management and future perspectives of research on this condition.     

Eprosartan for the treatment of hypertension

Antihypertensive agents are proven to reduce the cardiovascular risk of stroke, coronary heart disease and cardiac failure. The ideal antihypertensive agent should control all grades of hypertension and have a placebo-like side effect profile. Angiotensin II (AII) receptor antagonists are a relatively new class of antihypertensive agent that block AII Type 1 (AT₁) receptors, and reduce the pressor effects of AII in the vasculature. By this mechanism, they induce similar pharmacological effects compared with angiotensin-converting enzyme (ACE) inhibitors, resulting in a lowering of blood pressure. However, AII receptor blockers differ from ACE inhibitors with respect to side effects, and induce less cough, a side effect which may be related to bradykinin or other mediators such as substance P. Within the class of AII blockers, eprosartan differs from other currently available agents in terms of chemical structure, as it is a non-biphenyl, non-tetrazole, non-peptide antagonist with a dual pharmacological mode of action. Eprosartan acts at vascular AT₁ receptors (postsynaptically) and at presynaptic AT₁ receptors, where it inhibits sympathetically stimulated noradrenaline release. Its lack of metabolism by cytochrome P450 enzymes confers a low potential for metabolic drug interactions and may be of importance when treating elderly patients and those on multiple drugs. In clinical trials, eprosartan has been demonstrated to be at least as effective in reducing blood pressure as the ACE inhibitor enalapril, and has significantly lower side effects. Eprosartan is safe, effective and well-tolerated in long-term treatment, either as a monotherapy or in combination with other antihypertensive drugs such as hydrochlorothiazide.     

Antihypertensive agents acting on the renin–angiotensin system and the risk of sepsis

AimsIn response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients.MethodsWe performed a nested case–control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs.ResultsFrom the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83–1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42–1.93). Users of ARBs, β-blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure.ConclusionsHypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk.     

神经内分泌抑制剂在慢性射血分数降低的心力衰竭患者中应用现状调查分析

目的 调查安徽省妇幼保健院慢性射血分数降低的心力衰竭（heart failure with reduced ejection fraction,HFrEF）患者神经内分泌抑制剂——血管紧张素转换酶抑制剂（angiotensin converting enzyme inhibitor,ACEI）或血管紧张素Ⅱ受体阻滞剂（angiotensin Ⅱ receptor blocker,ARB）、b受体阻滞剂（b-blocker,BB）和醛固酮受体拮抗剂（mineralocorticoid receptor antagonist,MRA）使用现状及其与指南的差距。方法 搜集并分析2018年1月—12月慢性HFrEF住院患者基本资料和3类神经内分泌抑制剂使用情况。结果 纳入研究的301例慢性HFrEF患者中,ACEI/ARB、BB和MRA使用率分别为77.4%,60.5%和94.0%,剂量达标率分别为44.2%,22.5%和100%。48.8%患者采用指南推荐的联合用药,包括1.3%两药联合（ACEI/ARB+BB）和47.5%三药联合（ACEI/ARB+BB+MRA）。结论 笔者所在医院慢性HFrEF患者神经内分泌抑制剂应用现状与指南仍有差异,ACEI/ARB和BB的使用率、剂量达标率和两药联合用药率均不足,而MRA使用过度,需进一步提高医师对指南的依从性。     

Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects

AIMS: To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)- and (S)-warfarin. RESULTS: Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)- and (S)-warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, infinity) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t(1/2) 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14). CONCLUSIONS: Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.     

血管紧张素转换酶抑制剂影响自发性高血压大鼠肾功能的机制

目的研究长期应用（4wk）卡托普利（30mg·kg-1）、依那普利（20mg·kg-1）和福辛普利（20mg·kg-1）3种血管紧张素转换酶抑制剂（ACEI）对自发性高血压大鼠（SHR）肾功能的影响以及与肾素-血管紧张素-醛固酮系统（RAA）、激肽释放酶-激肽系统（K-K）及前列腺素系统（PGS）的可能关系。方法测定血清及尿中的肌酐以计算肾小球滤过率、用放免法测定上述系统中有关活性物质在血浆、肾脏及尿中的浓度。结果3种ACEI均显著地降低SHR的血压。依那普利及福辛普利处理后SHR肌酐清除率分别为（370±112）及（380±110）ml·d-1，高于未处理SHR的滤过率（260±110，P＜0.05）。SHR用依那普利或福辛普利处理后血浆肾素活性及血管紧张素系Ⅰ（ATⅠ）浓度分别为（41±38）、（17±7）nmol·L-1·h-1及（12±8）、（14±10）nmol·L-1。肾脏肾素活性及ATⅠ浓度分别为（146±27）、（139±31）nmol·g-1蛋白·h-1及（85±25）、（95±23）nmol·g-1蛋白，均高于未处理组（P＜0.05）。SHR尿醛固酮排泄量在用卡托普利或依那普利处理后分别为（0.9±0.7）及（0.9±0.6）nmol·d-1，降至正常大鼠的水平，且低于未处理SHR（P＜0.05）。结论RAA在ACEI改善肾脏功能作用中起主要作用，而K-K及PGs不起重要作用。     

新型冠状病毒肺炎与血管紧张素转化酶2的研究现状

自2019年底起，新型冠状病毒肺炎（Coronavirus disease 2019，COVID-19）病例席卷全球。该病毒为β属冠状病毒，基因特征与严重急性呼吸综合征冠状病毒（Severe Acute Respiratory Syndrome Coronavirus，SARS-CoV）有较高相似性，被命名为2019新型冠状病毒（2019 Novel Coronavirus，2019-nCoV）或严重急性呼吸综合征冠状病毒-2（SARS-CoV-2），主要通过棘突蛋白介导与宿主血管紧张素转化酶2（angiotensin-converting enzyme 2，ACE2）受体结合侵犯人体。ACE2与COVID-19感染密切相关，既是SARS-CoV-2感染人体的关键靶点，ACE2表达多寡也是影响COVID-19患者疾病严重程度和死亡率的重要因素。因此靶向ACE2和肾素-血管紧张素系统（renin-angiotensin system，RAS）的诸多上市药物和在研药物，如血管紧张素转化酶抑制剂（angiotensin-converting enzyme inhibitor，ACEI）、血管紧张素受体拮抗剂（angiotensin receptor blocker，ARB）、重组人ACE2、Ⅱ型跨膜丝氨酸蛋白酶（type II transmembrane serine proteases，TMSPSS2）抑制剂、特异性中和抗体等都有可能成为治疗COVID-19的可行策略。此外，依据现有证据并不建议合并高血压的轻症COVID-19确诊病例或疑似病例轻易停用ACEI/ARB，以免造成血压波动。