RAAS Cascade Overview
The RAAS cascade begins in the kidney and generates a sequence of vasoactive peptides through enzymatic cleavage.
The Classic Cascade (Harmful Arm)
Angiotensinogen (liver) is cleaved by Renin (kidney juxtaglomerular cells) to produce Angiotensin I (10 amino acids, inactive). Angiotensin I is then converted by ACE (Angiotensin-Converting Enzyme, lung endothelium) into Angiotensin II (8 amino acids), the primary effector of the RAAS harmful arm. Angiotensin II binds AT1 receptors to cause vasoconstriction, aldosterone release, sodium retention, inflammation, and fibrosis.The Counter-Regulatory Arm (Protective)
ACE2 (expressed in heart, lung, kidney, endothelium) converts Angiotensin II into Angiotensin (1-7) (7 amino acids), which opposes Angiotensin II via the Mas receptor. Ang(1-7) is vasodilatory, anti-inflammatory, anti-fibrotic, and cardioprotective. ACE2 also converts Angiotensin I into Angiotensin (1-9), which is further cleaved to Ang(1-7). This ACE2/Ang(1-7)/Mas axis is the focus of intensive cardiovascular and renal research, and became globally significant as ACE2 is the SARS-CoV-2 entry receptor.The Aldosterone Branch
Angiotensin II stimulates the adrenal cortex to release Aldosterone, a mineralocorticoid that drives sodium reabsorption and potassium excretion in the kidney collecting duct, raising plasma volume and blood pressure. This aldosterone component is why RAAS blockade is so effective in hypertension and heart failure.RAAS Peptide Components
Each peptide in the RAAS cascade has a distinct receptor profile and biological role.
Angiotensin II (AT1/AT2)
The central effector. AT1 receptor activation drives vasoconstriction, aldosterone release, sympathetic activation, reactive oxygen species (ROS) generation, inflammation, and cardiac/vascular remodeling. AT2 receptor activation (opposing AT1) promotes vasodilation, apoptosis, and anti-proliferation. The AT1:AT2 balance determines the net cardiovascular effect. See: Angiotensin II.Angiotensin (1-7), Protective Arm
The counter-regulatory peptide. Binds Mas receptor and AT2 receptor to oppose Ang II. Actions: vasodilation, natriuresis (sodium excretion), anti-fibrosis, anti-inflammation, endothelial protection, cardiac protection, improved insulin sensitivity. Generated from Ang II via ACE2, or from Ang I via ACE2 + Neprilysin. See: Angiotensin (1-7).Angiotensin (1-9)
Generated from Angiotensin I by ACE2 (removes the C-terminal Leu). Binds AT2 receptor. Anti-hypertrophic effects in heart tissue, counters Ang II-induced cardiac remodeling. The research relevance is primarily as an ACE2 activity marker and as a source of Ang(1-7) via further cleavage. See: Angiotensin (1-9).Angiotensin IV (AT4 axis)
A metabolite of Angiotensin III, binding the AT4 receptor (IRAP, Insulin-Regulated Aminopeptidase). AT4 receptor activation modulates memory consolidation, cognitive function, and renal cortical blood flow. Angiotensin IV is at the intersection of RAAS cardiovascular biology and neuromodulatory peptide research. See: Angiotensin IV.Alamandine
A recently characterized RAAS peptide (analog of Ang(1-7), with Ala instead of Asp at position 1) that binds the MrgD receptor rather than Mas. Vasodilatory, anti-fibrotic, and cardioprotective with a distinct receptor profile from Ang(1-7). See: Alamandine.Bradykinin (RAAS-adjacent)
ACE inhibitors also block bradykinin degradation (bradykinin is cleaved by ACE), elevating bradykinin levels. Bradykinin causes vasodilation via B2 receptors and is responsible for the cough and angioedema side effects of ACE inhibitors. Bradykinin and the RAAS are mechanistically coupled at the ACE enzyme level. See: Bradykinin.Calculate your RAAS System dose Vial strength, BAC water, exact syringe draw in IU. Free, no signup. Open Calc →
RAAS Drug Targets
The RAAS is the most heavily targeted pathway in cardiovascular pharmacology.
ACE Inhibitors (ACEi)
Block ACE, reducing Ang II production and raising bradykinin. Examples: lisinopril, ramipril, enalapril. First-line for hypertension, heart failure, diabetic nephropathy. Side effect: bradykinin-mediated cough (~10-20% of users), angioedema (rare).Angiotensin Receptor Blockers (ARBs)
Block the AT1 receptor directly without affecting ACE or bradykinin. Examples: losartan, valsartan, olmesartan. Preferred when ACEi cough is intolerable. Similar efficacy to ACEi for cardiovascular endpoints. Do not raise bradykinin.Renin Inhibitors
Block the cascade at its source. Aliskiren is the only approved direct renin inhibitor. Less widely used due to limited outcome data vs ACEi/ARBs.Aldosterone Antagonists (MRA)
Block aldosterone at the mineralocorticoid receptor. Spironolactone, eplerenone. Reduce sodium retention, fibrosis, and sympathetic activation. Critical in heart failure with reduced ejection fraction.ACE2 Activators (Emerging)
Research focus: activating ACE2 to increase Ang(1-7) production. Diminazene aceturate (DIZE) is the most studied ACE2 activator in preclinical models. Direct Ang(1-7) administration and Ang(1-7) analogs (like Alamandine) are also being investigated as RAAS-protective therapeutics.ACE2, SARS-CoV-2, and Protective RAAS Research
ACE2 gained widespread attention as the entry receptor for SARS-CoV-2. The spike protein binds ACE2 with high affinity, leading to ACE2 downregulation upon infection. This ACE2 downregulation shifts the RAAS balance toward the harmful Ang II-dominant state, contributing to the cardiovascular, pulmonary, and inflammatory manifestations of COVID-19.
Ang(1-7) in COVID-19 Context
The reduction of ACE2 activity during SARS-CoV-2 infection depletes Ang(1-7), removing its protective vasodilatory and anti-inflammatory effects. Multiple clinical trials explored Ang(1-7) administration as a therapeutic intervention in COVID-19-related ARDS and cardiovascular injury, establishing RAAS biology firmly in mainstream medical research.Ongoing RAAS Peptide Research Areas
1. Ang(1-7) as a standalone therapeutic for heart failure, renal protection, and pulmonary hypertension 2. Alamandine's MrgD receptor as a novel cardiovascular target 3. AT2 receptor agonists as anti-fibrotic agents 4. ACE2 gene therapy for chronic RAAS dysregulation 5. Angiotensin IV / AT4 axis in memory and cognitive functionRAAS in Peptide Research Context
For peptide researchers, the RAAS represents one of the most clinically validated peptide signaling systems in human physiology. Several direct research angles:
Vasoactive Peptide Stacks
VIP (vasoactive intestinal peptide), Adrenomedullin, and Apelin all interact with the cardiovascular system and can be considered in the context of RAAS balance, particularly the Ang(1-7)/Mas axis which shares overlapping vasodilatory, anti-inflammatory, and renal-protective targets.BPC-157 and RAAS Crosstalk
BPC-157 has been studied for its effects on NO (nitric oxide) production and vascular tone, which intersects with Angiotensin II's vasoconstrictor mechanisms. Some animal data suggests BPC-157 may modulate the NO/RAAS interface in ischemia-reperfusion models.Angiotensin (1-7) as a Research Peptide
Ang(1-7) is commercially available as a research peptide. Reconstituted at 0.5-1 mg/mL in sterile saline, it is used in animal cardiovascular research. Human clinical data exists (Phase 2 trials in cancer cachexia, post-COVID, heart failure), making it one of the more clinically-proximate RAAS peptides in active research.References
- [1]Ferrario CM, Jessup J, et al. "Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2." Circulation. 2005.
- [2]Santos RA, et al. "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas." PNAS. 2003.
- [2]Oudit GY, Bhatt DL. "Mechanism of cardiovascular manifestations of COVID-19 infection." Nature Reviews Cardiology. 2021.
- [3]Patel VB, et al. "Angiotensin-converting enzyme 2 is a critical determinant of angiotensin II-induced loss of vascular smooth muscle cells." Arteriosclerosis, Thrombosis, and Vascular Biology. 2014.
- [4]Passos-Silva DG, et al. "Angiotensin-(1-7): beyond the cardioprotective effects in the heart." Therapeutic Advances in Cardiovascular Disease. 2013.
Key Terms
The Renin-Angiotensin-Aldosterone System (RAAS) is the master hormonal cascade governing blood pressure, fluid balance, …
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