Angiotensin II: Central Regulator of Blood Pressure and Fluid Balance

Angiotensin II (Ang II) is the principal effector peptide of the renin-angiotensin-aldosterone system (RAAS), a critical hormonal cascade regulating blood pressure, fluid/electrolyte homeostasis, and vascular tone.

RAAS Cascade

1. Renin Release: Juxtaglomerular cells (kidney) release renin in response to ↓ renal perfusion pressure, ↓ NaCl delivery to macula densa, or β₁-adrenergic stimulation.
2. Angiotensinogen → Ang I: Renin cleaves hepatic angiotensinogen → inactive decapeptide Ang I.
3. ACE Conversion: Angiotensin-converting enzyme (ACE) on pulmonary endothelium cleaves Ang I → Ang II (octapeptide).
4. Alternative Pathways: Chymase (mast cells, heart) also generates Ang II; ACE2 degrades Ang II → Ang-(1-7) (vasodilatory, counter-regulatory).

Ang II Actions (via AT₁ Receptor)

• Vasoconstriction: Direct vascular smooth muscle contraction → ↑ TPR → ↑ BP (rapid, seconds).
• Aldosterone Release: Adrenal cortex → ↑ Na⁺/H₂O reabsorption in collecting duct → ↑ blood volume → ↑ BP (slow, hours-days).
• ADH Release: Posterior pituitary → water retention.
• Sympathetic Activation: Central (↑ norepinephrine release) + peripheral (presynaptic facilitation).
• Renal Effects: Efferent arteriolar constriction → maintains GFR; proximal Na⁺ reabsorption.
• Remodeling: Vascular hypertrophy, cardiac fibrosis, inflammation, oxidative stress (chronic).

Clinical Targeting

• ACE Inhibitors (lisinopril, ramipril): Block Ang I → Ang II conversion. ↑ Bradykinin (cough, angioedema).
• ARBs (losartan, valsartan): Block AT₁ receptor. No bradykinin accumulation.
• ARNI (sacubitril/valsartan): Neprilysin inhibitor + ARB – enhances natriuretic peptides.
• Direct Renin Inhibitor (aliskiren): Upstream blockade.
• Mineralocorticoid Receptor Antagonists (spironolactone, eplerenone): Block aldosterone effects.

Pathophysiology

RAAS overactivation drives hypertension, heart failure, diabetic nephropathy, atherosclerosis. Blockade is cornerstone therapy.