When the juxtaglomerular apparatus senses low arteriolar pressure, low distal sodium or sympathetic activation, it secretes renin, which is a protease, not a vasoconstrictor.Starting point: the juxtaglomerular apparatus (JGA) on the afferent arteriole wall senses three things simultaneously —
Any one signal triggers → JGA secretes renin into the blood.
Key: renin itself is not a vasoconstrictor — it's a protease; the true hormone is still downstream.
2 · Renin → AT-I
Liver-synthesised angiotensinogen (~ 60 kDa large protein) continuously floats in the blood (constant concentration, not rate-limiting).Renin = a chemical scissors that cuts the N-terminal 10 amino acids of angiotensinogen → produces angiotensin I (AT-I, decapeptide).
AT-I has almost no activity — it's just an intermediate. The intensity of the whole system is determined by renin (enzyme) + substrate quantity (constant).
This is why plasma renin activity (PRA) is the key clinical measurement for distinguishing -related hypertension subtypes — low PRA + high aldosterone = primary aldosteronism; high PRA + high aldosterone = secondary (renal artery stenosis).
3 · ACE (lung) → AT-II
ACE on pulmonary vascular endothelium cuts 2 more amino acids off AT-I to make AT-II, the true hormone, which constricts arterioles, triggers aldosterone release and drives thirst.Angiotensin-converting enzyme (ACE) is mainly expressed on pulmonary vascular endothelium (small amounts in kidney + other vascular beds), and cleaves 2 more amino acids from AT-I → AT-II (octapeptide) — the true hormone effector.
AT-II does three things simultaneously:
1. Directly constricts arterioles (AT₁ receptor + smooth muscle calcium) → BP ↑ 2. Stimulates the adrenal cortex zona glomerulosa → aldosterone release 3. Acts on the hypothalamus → thirst + ADH (antidiuretic hormone) release + sympathetic ↑
ACE also degrades bradykinin — this is why ACEi (-prils) causes a cough in ~ 10-20% of patients (accumulated bradykinin irritates airways); using (-sartans) which directly block AT₁ receptors, doesn't affect bradykinin → no cough.
Red ✕ = ACEi block point; purple ✕ = ARB block point
4 · Aldosterone closes the loop
Aldosterone makes the collecting duct reabsorb more sodium and water and excrete more potassium; as pressure recovers, renin stops, closing a negative feedback loop that drugs block at 3 points.Aldosterone (a steroid hormone) acts on the terminal distal convoluted tubule + collecting duct principal cells:
Net effect: sodium-water retention → blood volume ↑ → cardiac output ↑ → BP ↑ → JGA senses BP recovery → renin secretion stops (negative feedback loop closed)
Clinical significance (3 points where drugs block the chain):
· ACEi (-prils) — block at ACE → entire downstream chain reduced → first-line for hypertension + renoprotection + heart failure · (-sartans) — block at AT₁ receptor → equivalent effect, no cough · MRA (spironolactone / eplerenone) — block at the aldosterone MR receptor → resistant hypertension / HFrEF / primary aldosteronism / watch hyperkalaemia + male gynaecomastia
The whole is the difference between 200 mmHg hypertension and 100 mmHg — understanding this loop, you understand why ACEi/ARB are the most commonly prescribed cardiovascular + renal drugs.