Angiotensin II Peptide

Ang II is a linear octapeptide with aspartic acid at the N-terminus and phenylalanine at the C-terminus. Hydrophobic residues are concentrated at the C-terminus, while hydrophilic residues are distributed at the N-terminus, endowing it with high receptor affinity, wide tissue distribution, and short half-life (1-2 minutes). The generation process is as follows: renin (renal glomerular cells) → shear angiotensinogen (liver) → angiotensin I (decapeptide) → ACE (lung/endothelial cells) → Ang II (octapeptide); Metabolism is mainly degraded into inactive fragments by aminopeptidase and neutral endopeptidase (NEP).

Organizational distribution: Widely distributed throughout the body, the vascular endothelium/smooth muscle, kidneys (proximal tubules/glomeruli), adrenal cortex, heart, brain (hypothalamus/brainstem), liver, adipose tissue, and immune cells have the highest concentrations and are the core mediators of RAAS in circulation and local tissues.
Receptor expression: AT ₁ receptors (Gq coupled): widely expressed in vascular smooth muscle, myocardium, kidney, adrenal gland, brain, and liver, mediating major effects such as vascular constriction, proliferation fibrosis, inflammation, and hypertension; AT ₂ receptor: high expression during embryonic stage and low expression in adulthood (upregulated in pathology), mediating antagonistic effects such as relaxation, anti proliferation, anti-inflammatory, and apoptosis.

Ang II mainly activates downstream pathways such as MAPK/ERK, PI3K/AKT, NF - κ B, RhoA/ROCK through the AT ₁ receptor-Gq-PLC-IP ∝/DAG pathway, mediating multi system effects such as blood vessels, kidneys, heart, inflammation, sympathetic nervous system, etc.
Vasoconstriction pathway: Ang II → AT ₁ → Gq → PLC → IP ∝ → Endoplasmic reticulum Ca ² ⁺ release → Intracellular Ca ² ⁺ elevation → Smooth muscle contraction → Increased vascular resistance → Elevated blood pressure; Simultaneously activate RhoA/ROCK → inhibit myosin phosphatase → sustain smooth muscle contraction.

Proliferation fibrosis pathway: activation of MAPK/ERK, PI3K/AKT → smooth muscle/myocardial cell proliferation, collagen deposition, fibrosis, vascular/myocardial hypertrophy.
Inflammatory pathway: activation of NF - κ B → release of TNF - α, IL-6, IL-1 β, MCP-1 → vascular inflammation, endothelial injury, atherosclerosis.
Kidney water and sodium retention pathway: activate Na+/H+exchanger (NHE3), ENaC → increase of sodium and water reabsorption in proximal convoluted tubules → increase of blood volume → increase of blood pressure.
Sympathetic activation pathway: acts on the sympathetic center of the brainstem, adrenal medulla → norepinephrine, adrenaline release → vasoconstriction, increased heart rate, increased cardiac output → pressor.

Ang II is one of the strongest vasoconstrictor peptides in the body. Under physiological conditions, Ang II can rapidly regulate blood pressure and maintain blood pressure stability through the triple mechanism of vasoconstriction, water and sodium retention, and sympathetic activation, especially in cases of hypotension, blood loss, dehydration, and low salt diet.

Acute pressor: blood loss/dehydration → blood pressure drop → renin release → Ang II generation → systemic constriction of small arteries/veins (preferentially constricting skin/visceral blood vessels to protect heart and brain perfusion) → increased peripheral resistance → rapid increase in blood pressure; Acting on cerebral blood vessels → mild contraction, maintaining cerebral perfusion pressure.
Long term blood pressure maintenance: low salt diet → decreased blood sodium → activation of renin Ang II → increased renal sodium and water reabsorption → blood volume expansion → blood pressure maintenance; Simultaneously inhibiting renin release (negative feedback) to avoid excessive activation.

Ang II acts directly through the kidneys and releases aldosterone from the adrenal gland, precisely regulating sodium, water, and potassium metabolism, maintaining blood volume, osmotic pressure, and electrolyte balance.
Direct renal action: low concentration Ang II → activation of proximal tubule NHE3 → increased Na ⁺ reabsorption and H ⁺ excretion (HCO ∝⁻ reabsorption); High concentration → inhibits sodium water reabsorption (negative feedback).

Aldosterone release: Ang II → Adrenal cortex zona glomerulosa AT ₁ receptors → Aldosterone synthesis and release → Na ⁺ reabsorption and K ⁺ excretion in distal tubules/collecting ducts → Increased blood volume and decreased blood potassium.
Release of vasopressin: Ang II → hypothalamus/posterior pituitary gland → release of arginine vasopressin (ADH) → increased water reabsorption in the collecting duct → blood volume dilation and decreased osmotic pressure.

Mechanism of action: Direct activation of AT ₁ receptors → Strong vasoconstriction → Increased peripheral resistance → Rapid increase in blood pressure; Simultaneously inhibiting the release of inflammatory factors, improving vascular permeability, reducing fluid extravasation, and protecting organ perfusion.
Clinical efficacy: Phase III clinical trial (ATHOS-1) showed that the Ang II treatment group had a significantly higher blood pressure compliance rate (mean arterial pressure ≥ 65mmHg) than the control group (70% vs 25%), a 50% reduction in norepinephrine dosage, and a 15% reduction in 28 day mortality rate; For patients with septic shock combined with acute kidney injury, it can improve renal perfusion and reduce the risk of renal function deterioration.
Usage and dosage: intravenous infusion, starting dose 20ng/kg/min, adjusted according to blood pressure, maximum 80ng/kg/min; Half life of 1-2 minutes, continuous infusion is required, and blood pressure rapidly drops after discontinuation of medication.

Cardiogenic shock: sudden decrease in cardiac output, hypotension, and insufficient peripheral perfusion caused by myocardial infarction, heart failure, myocarditis, etc; Ang II acts as a second-line drug when norepinephrine is ineffective, as it enhances blood pressure, increases coronary perfusion, improves myocardial oxygen supply, reduces sympathetic nervous system excitation, and decreases myocardial oxygen consumption through potent vasoconstriction.
Vascular paralysis syndrome: excessive vasodilation, hypotension, and resistance to catecholamines after cardiac surgery, severe trauma, and burns; Ang II can quickly reverse vascular paralysis, restore vascular tone, increase blood pressure, and reduce the use of vasoactive drugs.

Hepatorenal syndrome (HRS): Cirrhosis/liver failure → visceral vasodilation, reduced effective circulating blood volume, renal hypoperfusion, renal failure; Ang II contracts visceral blood vessels, increases effective circulating blood volume, improves renal perfusion, enhances renal function, prolongs survival, and buys time for liver transplantation.
Hypotension during dialysis: rapid ultrafiltration, sudden decrease in blood volume, vasodilation → hypotension, dizziness, nausea, and interruption of dialysis during hemodialysis; Continuous infusion of small doses of Ang II during dialysis can maintain vascular tension, stabilize blood pressure, and ensure smooth dialysis.
Endocrine disorders: Addison's disease (adrenal insufficiency) → aldosterone deficiency, sodium and water loss, hypotension, hyperkalemia; Ang II can directly constrict blood vessels, increase blood pressure, and reduce sodium and water loss, serving as an adjuvant therapy for glucocorticoids/mineralocorticoids.