Renin-Angiotensin System and Alzheimer’s Disease Pathophysiology: From the Potential Interactions to Therapeutic Perspectives

2020 ◽  
Vol 27 (6) ◽  
pp. 484-511 ◽  
Author(s):  
Victor Teatini Ribeiro ◽  
Leonardo Cruz de Souza ◽  
Ana Cristina Simões e Silva
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzyme Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beneficial Effects

New roles of the Renin-Angiotensin System (RAS), apart from fluid homeostasis and Blood Pressure (BP) regulation, are being progressively unveiled, since the discoveries of RAS alternative axes and local RAS in different tissues, including the brain. Brain RAS is reported to interact with pathophysiological mechanisms of many neurological and psychiatric diseases, including Alzheimer’s Disease (AD). Even though AD is the most common cause of dementia worldwide, its pathophysiology is far from elucidated. Currently, no treatment can halt the disease course. Successive failures of amyloid-targeting drugs have challenged the amyloid hypothesis and increased the interest in the inflammatory and vascular aspects of AD. RAS compounds, both centrally and peripherally, potentially interact with neuroinflammation and cerebrovascular regulation. This narrative review discusses the AD pathophysiology and its possible interaction with RAS, looking forward to potential therapeutic approaches. RAS molecules affect BP, cerebral blood flow, neuroinflammation, and oxidative stress. Angiotensin (Ang) II, via angiotensin type 1 receptors may promote brain tissue damage, while Ang-(1-7) seems to elicit neuroprotection. Several studies dosed RAS molecules in AD patients' biological material, with heterogeneous results. The link between AD and clinical conditions related to classical RAS axis overactivation (hypertension, heart failure, and chronic kidney disease) supports the hypothesized role of this system in AD. Additionally, RAStargeting drugs as Angiotensin Converting Enzyme inhibitors (ACEis) and Angiotensin Receptor Blockers (ARBs) seem to exert beneficial effects on AD. Results of randomized controlled trials testing ACEi or ARBs in AD are awaited to elucidate whether AD-RAS interaction has implications on AD therapeutics.

scholarly journals Dual Blockade of the Renin-Angiotensin System: A Strategy that Should Be Reconsidered in Cardiorenal Diseases?

Nephron ◽  
2021 ◽  
pp. 1-8
Author(s):  
Mei Mei ◽  
Zulian Zhou ◽  
Qian Zhang ◽  
Yi Chen ◽  
Hongwen Zhao ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Individualized Therapy ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
System A ◽  
Receptor Blockers

Studies on pharmacological mechanisms demonstrated that a strategy of dual renin-angiotensin system (RAS) blockade may have a synergistic effect in the treatment of cardiorenal diseases and may reduce adverse reactions. However, some previous clinical studies reported that dual RAS blockade did not significantly benefit many patients with cardiorenal diseases and increased the risk of hyperkalemia, hypotension and renal function damage. Therefore, the current clinical guidelines suggest that the combined use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be used with caution in the clinic. However, these studies enrolled older patients with cardiovascular risk factors, and the results of these trials may not be generalized to the overall population. Some clinical evidence suggests that the combination of low-dose ACEIs and ARBs leads to more effective RAS blockade with few adverse effects. The advent of new RAS inhibitors with superior pharmacological effects provides a more suitable drug choice for individualized therapy for dual RAS blockade. Therefore, the choice of appropriate ARBs/ACEIs for individualized therapy based on patient condition may be a better way to improve the efficiency and safety of the dual RAS blockade strategy.

HFrEF pharmacological treatment: ACEIs and/or ARBs

ESC CardioMed ◽  
2018 ◽  
pp. 1844-1848
Author(s):  
Marc A. Pfeffer
Keyword(s):  
Heart Failure ◽  
Angiotensin Receptor Blockers ◽  
Antihypertensive Agents ◽  
Drug Effects ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Reduced Ejection Fraction

Several classes of inhibitors of the renin–angiotensin system were developed as antihypertensive agents. Following the early observations of favourable haemodynamic effects of angiotensin-converting enzyme inhibitors (ACEIs) in patients with congestive heart failure, a series of major randomized outcome trials demonstrated morbidity and mortality benefits of these agents across the spectrum of patients with heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor blockers (ARBs) were then also shown to have similar benefits with a suggestion of some incremental improvements when used together. However, in the trials that randomized patients to a proven dose of an ACEI plus either placebo or an ARB, the combination of the two inhibitors of the renin–angiotensin system resulted in more adverse drug effects without a meaningful improvement in clinical outcomes. This chapter reviews the fundamental underpinnings for use of either an ACEI or ARB to improve prognosis of patients with HFrEF.

Renin-Angiotensin-Aldosterone System and Migraine: A Systematic Review of Human Studies

2020 ◽  
Vol 27 (6) ◽  
pp. 512-519 ◽  
Author(s):  
Karina Lúcia Moreira Sassi ◽  
Laís Bhering Martins ◽  
Aline Silva de Miranda ◽  
Antonio Lucio Teixeira
Keyword(s):  
Systematic Review ◽  
Enzyme Inhibitors ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Migraine Treatment ◽  
Converting Enzyme Inhibitors ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
At1 Receptor Antagonists

Migraine is a common neurologic condition marked by recurrent episodes of headache. Its pathophysiology is highly complex involving neuronal, inflammatory and vascular mechanisms. The Renin-Angiotensin System (RAS) can modulate all these mechanism, being a potential pharmacological target for migraine treatment. We carried out a systematic review of the studies evaluating the involvement of RAS in patients with migraine. There is evidence from genetic studies exploring the relation between migraine and RAS-related genes and from clinical trials evaluating the efficacy of Angiotensin II Type 1 (AT1) receptor antagonists and angiotensin converting enzyme inhibitors in migraine prophylaxis. RAS seems to play a role in the pathophysiology of migraine, but more direct evidence is still missing.

scholarly journals Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes

2021 ◽  
Vol 22 (13) ◽  
pp. 6738
Author(s):  
Céline Delaitre ◽  
Michel Boisbrun ◽  
Sandra Lecat ◽  
François Dupuis
Keyword(s):  
Angiotensin Ii ◽  
Enzyme Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Cerebrovascular Diseases ◽  
Converting Enzyme Inhibitors ◽  
Beneficial Effects ◽  
Biased Signaling

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the β-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.

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