Therapeutic potential of angiotensin receptor blockers in hypertension

The renin–angiotensin–aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin II receptor blockers (ARBs) inhibit angiotensin II type 1 receptors and large clinical trials have shown that they are effective in many cardiovascular diseases including hypertension, heart failure, myocardial infarction and diabetic nephropathy. They lower blood pressure effectively, are very well tolerated and can be used as monotherapy or in combination with other drug classes for the treatment of hypertension. ARBs are particularly suitable for hypertensive patients with co-morbities such as diabetes, microalbuminuria, proteinuria, left ventricular hypertrophy and heart failure. Unlike angiotensin-converting enzyme inhibitors, ARBs do not cause persistent dry cough. For patients in whom angiotensin-converting enzyme inhibitors are indicated but not tolerated, an ARB should be considered. Periodic monitoring of renal function and electrolytes is required in patients treated with an ARB.     

Effects of combination of angiotensin receptor blocker and calcium channel blocker on ox-LDL levels and cardiovascular dysfunction in Dahl rats

In an effort to assess the cardiovascular benefits of combined angiotensin receptor blockage and calcium channel antagonism, we assessed the chronic effects of the angiotensin type 1 receptor blocker candesartan, the calcium channel blocker benidipine, and the use of a combination therapy in Dahl salt-sensitive (DS) rats. DS rats receiving a high salt diet were treated with either benidipine (4 mg/kg), candesartan (1 mg/kg) or both. Rat blood pressure was measured using a tail-cuff method. Following 12 weeks, the effect on heart weight, plasma-oxidized low-density lipoprotein (ox-LDL) level, endothelium-dependent vasorelaxation, and histology of the heart and aorta was assessed. Blood pressure, heart weight and plasma ox-LDL levels increased, while endothelium-dependent vasorelaxation decreased in the DS rats. Candesartan and benidipine inhibited the increase in blood pressure and heart weight, and the decrease in endothelium-dependent vasorelaxation. The use of benidipine alone or a combination significantly inhibited the increase in ox-LDL levels, whereas candesartan alone had no significant effect on ox-LDL levels. The present findings indicate that, if the monotherapy using ARB could not achieve adequate control of blood pressure, the combination therapy with ARB and benidipine provides the additional reductions in hypertension and cardiac hypertrophy. Moreover, the combination therapy inhibits cardiovascular dysfunction and ox-LDL levels more effectively than use of ARB alone. These results contribute to the possibility of lowering ox-LDL levels as a means of enhancing cardiovascular protection.     

Unmasking the potential of the angiotensin AT2 receptor as a therapeutic target in hypertension in men and women: What we know and what we still need to find out

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Pleiotropic effects of ARB in metabolic syndrome

Metabolic syndrome comprises of a cluster of several risk factors including abdominal obesity, dyslipidemia, elevated blood pressure, and insulin resistance. Many manifestations occur in sequence which is also referred to as the metabolic domino. Because the renin-angiotensin system (RAS) seems to be involved in this domino effect, RAS blockade by angiotensin II receptor blockers (ARB) offers a therapeutic tool for treating hypertension and ultimately the metabolic syndrome itself. In this paper, I describe the effects of ARBs on adiponectin, blood pressure, and fatty liver. Several clinical studies have reported that ARBs elevate adiponectin. ARBs that activate the PPARγ may be more effective than others. In terms of blood pressure, transient ARB administration may prevent the development of hypertension and high doses of ARB may regress mild hypertension. In terms of fatty liver, several research studies have indicated that ARBs may prevent triglyceride accumulation in liver. Again, ARBs that activate PPARγ may be more effective than others. Thus, PPARγ-activating ARBs offer the most hopeful treatment for metabolic syndrome. Further studies are needed to confirm this hypothesis.     

A single pill to treat postmenopausal hypertension? Not yet

Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism(s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk factors, such as dyslipidemias, visceral obesity and endothelial dysfunction. Recently it became apparent that in a large number of hypertensive postmenopausal women, their BP is not well controlled with conventional antihypertensive medications. A clear understanding of the complex pathogenesis of postmenopausal hypertension is needed in order to offer the best therapeutic options for these women.     

Clinical profile of eprosartan: a different angiotensin II receptor blocker

Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity.     

ACEI联合ARB治疗中重度原发性高血压的临床研究

目的分析血管紧张素转化酶抑制剂(ACEI)联合血管紧张素受体拮抗剂(ARB)治疗中重度原发性高血压的临床效果。方法将我院78例原发性高血压患者按照双盲法随机分为3组,分别采用ACEI、ARB和联合使用2种药物3种治疗方案。比较3组患者一般资料的差异,服用药物治疗前后心功能相关指标变化、血压变化和不良发应的发生情况。结果 3组患者服用药物治疗前一般情况的差异没有统计学意义。服用药物前后3组患者心功能各项指标都有显著提升,ACEI组和ARB组改善程度接近,联合组的改善程度比ACEI组和ARB组效果好,差异有统计学意义。3组血压都明显下降,前2组血压下降程度相似,血压接近正常高值,联合组血压下降到正常值范围。3组患者发生不良反应的情况基本相似,联合组并未产生更加严重或频繁的不良反应。结论本研究通过数据证明,服用ACEI联合ARB类药物治疗原发性高血压有着显著的临床疗效。     

Drospirenone, a new progestogen, for postmenopausal women with hypertension

The prevalence of hypertension increases in women after the menopause. Associated with the rise in postmenopausal blood pressure (BP) are increased salt sensitivity and imbalance between the renin-angiotensin-aldosterone system and nitric oxide pathways that lead to sodium and water retention. Drospirenone is the first synthetic progestogen with antialdosterone activity similar to natural progesterone. Drospirenone counteracts the salt- and water-retaining effects of estrogen and causes natriuresis, which leads to a reduction in BP. In preclinical studies as well as early efficacy studies (for menopausal symptoms), drospirenone exhibited antihypertensive and natriuretic effects. Subsequent clinical trials in postmenopausal women proved that drospirenone with 17beta-estradiol has a significant BP-lowering effect in untreated hypertension and has additive effects when coadministered with ACE inhibitors, angiotensin II type 1 receptor antagonists and thiazide diuretics. The lowest effective dose of drospirenone for reduction in BP is 2mg, a dose that is also protective of the uterus in women treated with estrogen therapy. Additionally, clinical trials have shown that drospirenone up to 3 mg/day has an acceptable safety profile with no clinically significant elevations in plasma potassium in patients with concomitant NSAID use, diabetes mellitus or mild to moderate renal insufficiency. In addition to effectively relieving menopausal symptoms and lowering BP, drospirenone reduces bodyweight and lipoprotein concentrations. Thus, drospirenone is a unique progestogen that confers the additional benefit of BP reduction, an effect that could lead to potential benefit with respect to some cardiovascular risk concerns in women taking hormone therapy.     

Therapeutic potential of angiotensin receptor blockers in hypertension

The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin II receptor blockers (ARBs) inhibit angiotensin II type 1 receptors and large clinical trials have shown that they are effective in many cardiovascular diseases including hypertension, heart failure, myocardial infarction and diabetic nephropathy. They lower blood pressure effectively, are very well tolerated and can be used as monotherapy or in combination with other drug classes for the treatment of hypertension. ARBs are particularly suitable for hypertensive patients with co-morbidities such as diabetes, microalbuminuria, proteinuria, left ventricular hypertrophy and heart failure. Unlike angiotensin-converting enzyme inhibitors, ARBs do not cause persistent dry cough. For patients in whom angiotensin-converting enzyme inhibitors are indicated but not tolerated, an ARB should be considered. Periodic monitoring of renal function and electrolytes is required in patients treated with an ARB.     

Pharmacological profiles and clinical effects of olmesartan medoxomil, a novel angiotensin II receptor blocker

Olmesartan medoxomil is a new angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is converted to the active metabolite olmesartan. Olmesartan does not undergo further metabolism and does not interact with cytochrome P450 enzymes. Olmesartan is a potent ARB with high selectivity for the type 1 (AT(1)) receptor subtype and shows insurmountable antagonism against the AT(1) receptor in vascular tissues. This antagonistic mode, which could be attributed to tight binding of this drug to the receptor, would underlie the potent and persistent action of olmesartan medoxomil in vivo. In fact, oral administration of olmesartan medoxomil produces a potent and long-lasting antihypertensive action without inducing tachycardia. The preventive effects of olmesartan medoxomil on end-organ damage in the kidney, heart, and blood vessels have been demonstrated in various animal models. In clinical studies, olmesartan medoxomil is shown to be well tolerated and have an excellent safety profile that is comparable to that of placebo. Head-to-head comparisons with other ARBs (losartan, valsartan, irbesartan, and candesartan cilexetil) conducted in the United States and Europe have revealed that olmesartan medoxomil is superior to these other ARBs in lowering blood pressure. These facts suggest that olmesartan medoxomil would be beneficial for the treatment of hypertension and other end-organ diseases.     

Economic benefits of treating high-risk hypertension with angiotensin II receptor antagonists (blockers)

Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most patients with high- or very high-risk hypertension have multiple cardiovascular risk factors with or without accompanying subclinical organ damage or established cardiovascular or renal disease. Patients with severe hypertension or with moderate hypertension and one to two additional risk factors have absolute 10-year risks of cardiovascular disease of 21-30% and 15-20%, respectively. Current European treatment guidelines recommend that antihypertensive therapy be initiated rapidly and aggressively in patients with high-risk hypertension. Most patients require two or more antihypertensive agents to achieve the strict blood pressure target of <130/80 mmHg. This article reviews the existing cost-effectiveness data on the use of angiotensin II receptor antagonists (blockers) [ARBs] in patients with high-risk hypertension. Aggressive ARB treatment of patients in the early (microalbuminuric) stages of diabetic nephropathy has a significant renoprotective effect, delaying the onset of overt (proteinuric) nephropathy. By slowing the progression of these patients to end-stage renal disease, substantial cost savings can be made. There is a paucity of cost-effectiveness data regarding the use of fixed-dose ARB plus thiazide diuretic combination therapies. Longitudinal cost-benefit studies of this attractive and efficacious first-line treatment option are needed.     

Improving treatment adherence to antihypertensive therapy: the role of single-pill combinations

INTRODUCTION: The majority of patients with hypertension require combination therapy to achieve their blood pressure (BP) goal. Studies have consistently shown that polypharmacy and complex treatment regimens have a detrimental effect on treatment compliance, adherence and persistence (herein referred to as treatment adherence). AREAS COVERED: This paper reviews the available clinical evidence, as well as guidelines, which propose combinations of an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor plus a calcium channel blocker (CCB) or diuretic. EXPERT OPINION: ARBs are associated with better tolerability compared with ACE inhibitors, and data suggest that ARB/CCB combinations may be better tolerated than CCB monotherapy. The use of true once-daily single-pill combination therapy with effective and well-tolerated agents will reduce pill burden, simplify treatment regimens and improve treatment adherence, which will, in turn, help patients to reach and maintain their BP target and achieve the short- and long-term treatment goal of cardiovascular risk reduction.     

Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension.

Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists (CAs) and blockers of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (ARBs)] are widely used today to initiate antihypertensive treatment but, when given as monotherapy, do not suffice in most patients to normalise blood pressure (BP). Combining a CA and either an ACE-inhibitor or an ARB considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. Several fixed-dose combinations are available (CA + ACE-inhibitors: amlodipine + benazepril, felodipine + ramipril, verapamil + trandolapril; CA + ARB: amlodipine + valsartan). They are expected not only to improve BP control, but also to facilitate long-term adherence with antihypertensive therapy, thereby providing maximal protection against the cardiovascular and renal damage caused by high BP.     

Telmisartan: just an antihypertensive agent? A literature review

INTRODUCTION: The modulation of the renin angiotensin aldosterone system (RAAS) is an important pathway in managing high blood pressure, and its overexpression plays a key role in target end-organ damage. Telmisartan is an angiotensin II receptor blocker (ARB) with unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a significant and 24-h sustained reduction of blood pressure. Telmisartan has well-known antihypertensive properties, but there is also strong clinical evidence that it reduces left ventricular hypertrophy, arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection. AREAS COVERED: This paper reviews telmisartan's pharmacological properties in terms of efficacy for hypertension control and, importantly, focuses on its new therapeutic indications and their clinical implications. EXPERT OPINION: ONTARGET (ongoing telmisartan alone and in combination with ramipril global endpoint trial) demonstrated, that telmisartan confers cardiovascular protective effects similar to those of ramipril, but with a better tolerability. Moreover, recent investigations focused on the capability of telmisartan to modulate the peroxisome proliferator-activated receptor-gamma (PPAR-γ), an established target in the treatment of insulin resistance, diabetes and metabolic syndrome, whose activation is also correlated to anti-inflammatory and, finally, anti-atherosclerotic properties. Telmisartan shows peculiar features that go beyond blood pressure control. It presents promising and unique protective properties against target end-organ damage, potentially able to open a scenario of new therapeutic approaches to cardiovascular disease.     

Vaccination against high blood pressure

Despite the attractiveness of a vaccination strategy for the treatment of high blood pressure, and many decades of research, attempts to translate this strategy to hypertension management have been unsuccessful. Immunization against components of the renin angiotensin system offers the prospect of improved long-term control of hypertension because efficacy does not require daily compliance with oral medication. Moreover, such a strategy may provide therapeutic benefits beyond blood pressure control, such as improved prevention and treatment of heart failure, and cardiovascular, cerebrovascular, and renal disease. However, despite these potential advantages, there are a number of concerns about the safety and efficacy of this approach. Renin immunization demonstrated effective blood pressure reduction in animal models of hypertension but was accompanied by autoimmune disease of the kidney. Moreover, there are theoretical arguments that angiotensin immunization may have limited effectiveness and clinical studies confirmed these limitations. Vaccination against the angiotensin II type 1 receptor is another possible approach but has yet to undergo clinical evaluation. Thus, the role of vaccination against renin angiotensin system components in hypertension management remains to be established.     

ACE inhibitors,angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.     

Candesartan cilexetil – a review of effects on cardiovascular complications in hypertension and chronic heart failure

ABSTRACT

Therapeutic interventions that block the renin–angiotensin–aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk factors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24?h blood pressure (BP) control with a trough:peak ratio close to 100%.

Scope: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF).

Findings: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction ≤ 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF.

Conclusions: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complica­tions across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.     

Does the angiotensin II receptor antagonist losartan improve cognitive function?

Newer classes of antihypertensive agents, such as angiotensin II receptor antagonists, may offer benefits to patients in addition to their ability to lower blood pressure. It is accepted that chronic hypertension contributes to the development of cerebrovascular and cardiovascular disease, and several studies have demonstrated a link between hypertension and reduced cognitive function, especially in patients not receiving antihypertensive medication. In an initial clinical trial, the angiotensin II receptor antagonist losartan was shown to improve cognitive function in patients with hypertension, including in those who were elderly (up to 73 years of age). This effect cannot be explained by a reduction in blood pressure alone and is likely to involve interactions with the diverse biological actions of the renin-angiotensin system. Improving or maintaining cognitive function in patients with hypertension may translate into economic benefits beyond those expected due to blood pressure control, and would result in considerable quality-of-life benefits for the aging population.     

Cardioprotective effects of telmisartan in uncomplicated and complicated hypertension

The development of angiotensin II receptor blockers (ARB) as a new class of drugs for the management of hypertension has elicited the attention of many clinicians worldwide with the aim of improving blood pressure (BP) control as well as cardiovascular protection. Among ARB telmisartan has been shown to be characterised by an antihypertensive efficacy fully covering the 24-hour period, thereby allowing to antagonise the adverse effects of early morning BP rise on cardiovascular risk. Other specific effects of the drug are represented by its favourable metabolic profile (particularly on insulin sensitivity) and neutral effects on sympathetic cardiovascular function. These properties are coupled with cardioprotective effects, documented by the evidence that the drug: 1) is effective in favouring the regression of cardiac and vascular organ damage, 2) reduces arterial stiffness and improves vascular distensibility and 3) reverses the endothelial dysfunction typical of the hypertensive state particularly when complicated by renal failure, diabetes, obesity or metabolic syndrome. Several of these properties can account for the results of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), documenting the beneficial effects on the drug on cardiovascular morbidity and mortality.     

Renin–angiotensin system inhibitor and statins combination therapeutics – what have we learnt?

Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin–angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.