Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment

Abstract

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

“…The RAS plays a significant role in the regulation of blood pressure and sodium and water homeostasis and occurs as (1) circulating hormonal system, (2) local or paracrine RAS expressed in many organs (both in the CNS and in the periphery), and (3) intracellular or intracrine RAS in several cell types [ 25 , 26 ]. The RAS comprises different peptides with opposing biological effects ( Figure 3 ).…”

“…The increase in the activity of one axis results in the decrease of the other [ 26 , 29 , 30 ]. Importantly, disturbance of the balance between the deleterious and the protective axis with the predominance of the ACE/Ang II/AT 1 R axis leads to many pathologies, including metabolic (diabetes mellitus), renal, cardiovascular (heart failure, myocardial infarction, hypertension), lung, hepatic, digestive, endocrine, neurodegenerative, hematological, reproductive, and muscular disease [ 4 , 26 , 30 , 31 , 32 ]. Even if the classic arm plays an important and unpleasant role in many disease states of humans, it is not per se deleterious.…”

“…The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection was rapidly spreading worldwide and led to over a hundred million detected infections and more than 6,200,000 deaths by 26 May 2022 ( (accessed on 5 May 2022)). Problems with vaccination of part of the population and mutations of the virus mean that SARS-CoV-2 infections may continue for many more years [ 26 ]; new promising therapies against COVID-19 are constantly being proposed. Recently, many studies have been published about the relationship between the RAS and the pathophysiology and severity of COVID-19.…”

The Endothelium and COVID-19: An Increasingly Clear Link Brief Title: Endotheliopathy in COVID-19

“…Due to SARS-CoV-2’s mechanism of infection via the ACE-2 receptor, one of the scientific community’s primary concerns has been the impact of RAS drugs on COVID-19 morbidity and mortality rates. Recently, two literature reviews highlighted the body of evidence showing that ACEIs and ARBs are not associated with an elevated risk of infection, greater disease severity, or a worse prognosis [ 112 , 113 ]. Moreover, recently published preclinical and clinical data indicate that ACEIs and ARBs are associated with a better COVID-19 outcome by reducing inflammatory responses and by triggering mechanisms that counteract viral entry.…”

“…Moreover, recently published preclinical and clinical data indicate that ACEIs and ARBs are associated with a better COVID-19 outcome by reducing inflammatory responses and by triggering mechanisms that counteract viral entry. However, this hypothesis require further support, and strategies that directly activate RAS anti-inflammatory components (such as soluble ACE2, angiotensin 1–7 analogues, and Mas or AT2 receptor agonists) are now emerging [ 113 ].…”