Brain angiotensin II and angiotensin IV receptors as potential Alzheimer’s disease therapeutic targets

Alzheimer’s disease (AD) is a neurodegenerative disorder that is multifactorial in nature. Yet, despite being the most common form of dementia in the elderly, AD’s primary cause remains unknown. As such, there is currently little to offer AD patients as the vast majority of recently tested therapies have either failed in well-controlled clinical trials or inadequately treat AD. Recently, emerging preclinical and clinical evidence has associated the brain renin angiotensin system (RAS) to AD pathology. Accordingly, various components of the brain RAS were shown to be altered in AD patients and mouse models, including the angiotensin II type 1 (AT1R), angiotensin IV receptor (AT4R), and Mas receptors. Collectively, the changes observed within the RAS have been proposed to contribute to many of the neuropathological hallmarks of AD, including the neuronal, cognitive, and vascular dysfunctions. Accumulating evidence has additionally identified antihypertensive medications targeting the RAS, particularly angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), to delay AD onset and progression. In this review, we will discuss the emergence of the RAS’s involvement in AD and highlight putative mechanisms of action underlying ARB’s beneficial effects that may explain their ability to modify the risk of developing AD or AD progression. The RAS may provide novel molecular targets for recovering memory pathways, cerebrovascular function, and other pathological landmarks of AD.

     

Are angiotensin receptor blockers neuroprotective?

Stroke is one of the leading causes of invalidism and death in the industrialized world. Among others, the reninangiotensin system (RAS) has been implicated in the pathogenesis and outcome of ischemic events, including stroke. Angiotensin II (Ang II), the major effector peptide of the RAS, exerts most of its well-defined physiologic and pathophysiologic actions, including those on the central and peripheral nervous system, through its Ang II type 1 (AT1) receptor subtype. This receptor not only contributes to stroke-related pathologic mechanisms (eg, hypertension, atherothrombosis, and cardiac hypertrophy) but also may be involved in postischemic damage to the brain. However, it has also been demonstrated that Ang II, via its AT2 receptor subtype, accelerates neuronal tissue regeneration after injury. In this article, we review the experimental evidence supporting the notion that blockade of brain AT1 receptors can be beneficial with respect to stroke incidence and outcome. We further delineate how AT2 receptors could be involved in neuronal regeneration following brain injury, such as stroke. In doing so, we also attempt to shed some light on the mechanisms by which AT1 receptor blockers, which leave the AT2 receptor unopposed, might exert protective actions in brain ischemia.     

Are angiotensin converting enzyme inhibitors and angiotensin receptor blockers becoming the treatment of choice in African-Americans?

African-American patients constitute a significant and important group who are at high risk for developing hypertension-related complications. The proportion of African-American patients succumbing to or suffering from cardiovascular, renal, and neurologic sequelae is unacceptably high. Therefore, it is extremely crucial to develop appropriate therapeutic strategies for this vital subset of our society. The renin-angiotensin system may play a role in the pathophysiology of hypertension-related diseases, and therefore drugs that block this system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, may have a special indication for African-American patients. Although these drugs may not be the most efficacious agents in terms of blood pressure reduction, they have a major benefit in offering target organ protection and arresting disease progression in the African-Americans. Hence, contrary to the old notions, drugs blocking the renin-angiotension system have an important place in the management of hypertension and related disorders in African-American patients.     

Do angiotensin II receptor antagonists substitute angiotensin converting enzyme inhibitors in the treatment of high blood pressure?

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AIIA) are both pharmacological groups that inhibit the actions of angiotensin II. ACEI prevent the formation of angiotensin II from angiotensin I, whereas A II A inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. A similar antihypertensive efficacy has been described for both groups but A II A drugs have a better safety profile above all due to the absence of dry cough. Despite the fact that evidence with ACEI is more conclusive, A II A seems to achieve the same protective effects on the target organ damage in hypertensive patients. At present, ACEI are the drugs of choice in the treatment of patients with cardiac dysfunction and failure. The information of ongoing trials with A II A will be of great value in deciding the optimal treatment for hypertensive patients with different cardiovascular diseases.     

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism?

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT₁R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall ≥ 10 mm Hg systolic or ≥ 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7 ± 8.1/3.3 ± 5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT₁ R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.     

Cardiac angiotensin II: an intracrine hormone?

The beneficial effects of renin-angiotensin system blockers on cardiac structure and function are usually explained based on the capacity of these drugs to interfere with angiotensin II at cardiac tissue sites. This review addresses to what degree cardiac angiotensin II generation occurs independently of the circulating renin-angiotensin system, and in particular tries to unravel where such generation might take place, taking into consideration that many reports suggest that angiotensin II is an intracrine hormone (ie, a hormone that is synthesized and acts intracellularly). It concludes that angiotensin II generation in the heart depends on circulating (ie, kidney-derived) renin, and occurs in interstitial fluid and possibly, in view of the recent discovery of renin-binding sites, on the cell surface of cardiac cells. Intracellular angiotensin II generation is unlikely to occur, in particular because angiotensinogen is not available in the cytosol.     

Involvement of insulin-regulated aminopeptidase in the effects of the renin–angiotensin fragment angiotensin IV: a review

For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin–angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT₁ receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP’s neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer’s disease, epilepsy and ischemia.     

Have angiotensin receptor blockers lived up to expectations?

Angiotensin receptor blockers (ARBs) were introduced after clinical trials showed angiotensin-converting enzyme inhibitors (ACEIs) to have extensive clinical benefits in a wide range of diseases. Consequently, it has been more difficult for clinical trials to demonstrate similar, enhanced or additive benefits of ARBs. However, ARBs were introduced with the hypothesis that they were likely a more effective method of interrupting the renin-angiotensin system and would result in enhanced outcomes. Clinical trials in high-risk vascular patients (after myocardial infarction), patients with heart failure and patients with nephropathy show the benefits of ACE inhibition. ARBs likely have similar benefits as ACEIs when used after myocardial infarction, in patients with heart failure and for management of diabetic nephropathy. However, ARBs generally remain a second-line treatment because it has been more difficult to demonstrate that ARBs prevent acute vascular events, such as myocardial infarction, together with the greater clinical trial evidence for ACE inhibition. The primary application of ACEIs over ARBs is reflected in the Canadian clinical guidelines for the management of patients with diabetes, hypertension, heart failure and following myocardial infarction. Until the completion of clinical trials, such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), that examine whether ARBs have vascular protective properties similar to ACEIs, it is unlikely that the clinical guidelines will change.     

Is the angiotensin ii type 2 receptor cerebroprotective?

Most of the deleterious effects of angiotensin II (Ang II) on blood pressure (BP), cardiovascular remodeling, and atherosclerosis are mediated by Ang II type 1 (AT1)-receptor activation. This explains why Ang-II-decreasing or blocking drugs have been successful in decreasing global cardiovascular morbimortality in patients with cardiac complications. However, in primary or secondary stroke prevention trials in patients with low cardiac risk, β-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazides and dihydropyridines, which increase Ang II. When compared with a b-blocker, an Ang II-increasing AT1-receptor blocker better protects against stroke but not against cardiac events, whereas an ACEI gives the same protection against both cardiac and cerebral events. This dissociation between blood-pressure-independent cardiac and cerebral protection between β-blockers or ACEIs versus AT1-blockers in patients with low cardiac risk can be best explained if, besides the beneficial vascular effect of AT1-receptor blunting, there is evidence of a beneficial effect of non-AT1-receptor activation. In this review, we present experimental evidence for AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.     

Is angiotensin II a proliferative factor of cardiac fibroblasts?

Angiotensin II has been implicated as an important factor in cardiac remodeling, particularly in the development of pathological left ventricular hypertrophy. It is generally assumed that angiotensin II is able to alter the phenotype of cardiac myocytes and fibroblasts, and several experiments have suggested that this peptide can particularly affect the proliferation of cardiac fibroblasts. However, a review of the published results indicates that there is no evidence that angiotensin II can directly trigger mitogenesis through activation of the cyclin-dependent pathway. The observed proliferative effect might well be caused by stimulation of the synthesis of growth or inflammatory substances like platelet-derived growth factor and cytokines, by integrin activation due to secreted extracellular matrix proteins, or by a combination of these mechanisms. Angiotensin II thus appears to differentiate cardiac fibroblasts into a growth substance-secreting phenotype.