scholarly journals Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System

2021 ◽  
Vol 12 ◽  
Author(s):  
Soraya Puglisi ◽  
Alessandro Rossini ◽  
Roberta Poli ◽  
Francesca Dughera ◽  
Anna Pia ◽  
...  
Keyword(s):  
Plasma Renin ◽  
Target Tissue ◽  
Protective Effects ◽  
Ang Ii ◽  
Osmotic Diuresis ◽  
Renin Angiotensin Aldosterone System ◽  
Glucose Lowering ◽  
Renin Angiotensin ◽  
Receptor Agonists

Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This “hybrid” diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.

scholarly journals The Influence of Long Term Hydrochlorothiazide Administration on the Relationship between Renin-Angiotensin-Aldosterone System Activity and Plasma Glucose in Patients with Hypertension

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Xu Xiao ◽  
Hong-jun Du ◽  
Wei-jian Hu ◽  
Peter X. Shaw
Keyword(s):  
Plasma Glucose ◽  
Density Lipoprotein ◽  
Plasma Renin ◽  
Ang Ii ◽  
Elevated Plasma ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Glucose Levels ◽  
One Year ◽  
The Relationship

Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension.Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment.Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (-0.26±0.26 mmol/L) and the nonelevated PRA group (-1.36±0.23 mmol/L) was statistically significant (P<0.05). The decrease of plasma glucose in the elevated Ang II group (-0.17±0.18 mmol/L) compared to the nonelevated Ang II group (-1.07±0.21 mmol/L) was statistically significant (P<0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P<0.05). The relative oxLDL level was not affected by the treatment.Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.

scholarly journals Glucose lowering and vascular protective effects of cycloset added to GLP-1 receptor agonists in patients with type 2 diabetes

2018 ◽  
Vol 1 (4) ◽  
pp. e00034 ◽  
Author(s):  
Mariam Alatrach ◽  
Christina Agyin ◽  
John Adams ◽  
Robert Chilton ◽  
Curtis Triplitt ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protective Effects ◽  
Glucose Lowering ◽  
Receptor Agonists

Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach

2018 ◽  
Vol 132 (5) ◽  
pp. 581-593 ◽  
Author(s):  
Douglas M. Bennion ◽  
Chad H. Jones ◽  
Alex N. Dang ◽  
Jacob Isenberg ◽  
Justin T. Graham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Angiotensin Ii ◽  
Receptor Agonist ◽  
At2 Receptor ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Compound 21 ◽  
Neuroprotective Actions

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood–brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4–9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

scholarly journals Renin-angiotensin-aldosterone system inhibitors – a realm of confusion in COVID-19

2021 ◽  
Vol 4 (Special2) ◽  
pp. 389-394
Author(s):  
Angela Madalina Lazar
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Current Knowledge ◽  
Angiotensin Receptor Blockers ◽  
Protective Effects ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Raas Inhibitors

Currently, there is a persisting dispute regarding the renin-angiotensin-aldosterone-system (RAAS) inhibitors' safety of use in COVID-19 pandemics. On one side, RAAS inhibitors appear to determine an overexpression of ACE2, the receptor of SARS-CoV-2. Therefore, they could increase the risk of SARS-CoV-2 infection and its degree of severity. On the other side, the discontinuation of RAAS leads to cardiovascular decompensation and has been discouraged by the major medical societies. Also, large-cohort studies report beneficial or at least neutral effects for the RAAS inhibitors in COVID-19 patients. Worldwide, millions of patients receive RAAS inhibitors for the treatment of hypertension and other important comorbidities. In this context, knowledge of the exact effect of these medications becomes of crucial significance. This paper aims to fill in a gap in the current knowledge and presents a putative mechanism by which RAAS inhibitor administration's beneficial results can be explained better. RAAS inhibitors can be beneficial, as they counteract the excessive detrimental activation of the classical angiotensin-converting enzyme (ACE) axis, decreasing the angiotensin II levels. The angiotensin receptor blockers (ARBs) increase the angiotensin II levels, while the angiotensin-converting enzyme inhibitors (ACEI) increase the angiotensin I levels; these substrates will compete with the SARS-CoV-2 for the ACE2 binding, decreasing the viral infectivity. In addition, following the RAAS inhibitors treatment, the up-regulated ACE2 will cleave these substrates (angiotensin I and II), particularly to angiotensin 1-7 that possesses vasodilator, protective effects.

scholarly journals Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2 Diabetes: Mechanistic Insights and Evidence from Major Clinical Trials

2021 ◽  
Author(s):  
Samara Skwiersky ◽  
Sandra Iwuala ◽  
Seeta Chillumuntala ◽  
Deborah Osafehinti ◽  
Jocelyne Karam
Keyword(s):  
Type 2 Diabetes ◽  
Secondary Analysis ◽  
Health Impact ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Randomized Controlled Studies ◽  
Multiple Trials ◽  
Added Benefit ◽  
Reduced Risk

With its alarmingly rising prevalence worldwide, type 2 diabetes has become a leading cause of morbidity and mortality around the planet. Efforts to prevent progression to diabetes in individuals at risk could have a significant positive public health impact. Multiple trials examining cardiovascular outcomes of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors revealed, in secondary analysis, a significantly reduced risk of new onset diabetes in participants receiving these agents. This glycemic protective effect is attributed to the known implication of RAAS in the development of insulin resistance and type 2 diabetes. The DREAM trial and the NAVIGATOR trial were two large randomized controlled studies examining, as primary outcome, the effect of Ramipril and Valsartan respectively on the incidence of diabetes in patients with prediabetes. Their results confirmed a favorable glycemic effect of RAAS inhibition agents and suggested a possible added benefit of diabetes prevention to their other several cardiovascular and blood pressure benefits.

scholarly journals How glucagon-like peptide 1 receptor agonists work

2021 ◽  
Author(s):  
Christine Rode Andreasen ◽  
Andreas Andersen ◽  
Filip Krag Knop ◽  
Tina Vilsbøll
Keyword(s):  
Body Weight ◽  
Therapeutic Potential ◽  
Clinical Effects ◽  
Glucose Lowering ◽  
Receptor Agonists ◽  
Reduce Body Weight ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

β-Pro7Ang III is a novel highly selective angiotensin II type 2 receptor (AT2R) agonist, which acts as a vasodepressor agent via the AT2R in conscious spontaneously hypertensive rats

2015 ◽  
Vol 129 (6) ◽  
pp. 505-513 ◽  
Author(s):  
Mark Del Borgo ◽  
Yan Wang ◽  
Sanja Bosnyak ◽  
Morimer Khan ◽  
Pia Walters ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Angiotensin Ii ◽  
Protein Binding ◽  
Binding Site ◽  
Spontaneously Hypertensive Rats ◽  
Protective Effects ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

We have synthesized a highly selective compound that is able to target a protein-binding site [called angiotensin (Ang) II type 2 receptor, AT2R] in the cardiovascular system. This research tool will enhance our ability to stimulate AT2R to produce protective effects against cardiovascular disease.

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