24 RAAS

# 25 RAAS

The renin-angiotensin-aldosterone system (RAAS) is the body's long-term regulator of blood pressure, sodium balance and extracellular fluid volume — and the most heavily examined endocrine cascade in MRCS Part A. Every step has a drug acting on it, and every drug has a side effect that loves to appear in SBAs.

The big picture

When the kidney senses falling perfusion or sodium delivery it releases renin, triggering a cascade with two effector hormones: angiotensin II (seconds — vasoconstriction) and aldosterone (hours — Na⁺ and water retention). The opposing system is atrial natriuretic peptide (ANP), released from atrial stretch in volume overload, causing vasodilation and natriuresis.

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Step 1 — Renin release

Renin is a proteolytic enzyme secreted by juxtaglomerular (JG) cells in the wall of the afferent arteriole. Three stimuli trigger release:

- ➡ Reduced renal perfusion pressure — JG cells act as baroreceptors (haemorrhage, renal artery stenosis).

- ➡ Reduced Na⁺ delivery to the macula densa — distal tubular cells abutting the afferent arteriole within the juxtaglomerular apparatus (JGA).

- ➡ Sympathetic stimulation via β1 receptors on JG cells — explains rapid RAAS activation in shock, exercise and stress.

Renin has no direct cardiovascular effect — it is purely an enzyme that cleaves angiotensinogen.

👩‍⚕️ The JGA is a classic exam favourite: macula densa (chemo/Na⁺ sensor), JG cells (renin secretors, baroreceptors), and extraglomerular mesangial cells (structural). Know which cell does what.

Step 2 — Angiotensinogen to Angiotensin I

Angiotensinogen is an α2-globulin made by the liver. Renin cleaves it into angiotensin I, a biologically inert decapeptide — a transport form waiting to be activated.

Step 3 — ACE converts AT-I to AT-II

Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase on vascular endothelium. The pulmonary capillary endothelium is the dominant reservoir — the lungs receive 100% of cardiac output, making them ideal for whole-body conversion.

ACE has a clinically important second substrate: bradykinin, a vasodilator. ACE degrades it. Block ACE and bradykinin accumulates — the basis of the ACEi cough and angioedema.

Step 4 — Angiotensin II effects

Angiotensin II is the workhorse. It acts at AT1 receptors (Gq-coupled) on multiple tissues:

Site	Effect
Vascular smooth muscle	Potent vasoconstriction → ↑ SVR, ↑ BP
Efferent arteriole (kidney)	Preferential constriction → maintains GFR when renal perfusion falls
Adrenal zona glomerulosa	Aldosterone release
Posterior pituitary	ADH (vasopressin) release
Hypothalamus	Thirst
Sympathetic nervous system	Augments noradrenaline release
Proximal convoluted tubule	Direct Na⁺/H⁺ exchange → Na⁺ reabsorption

The efferent arteriole point is high-yield. In renal artery stenosis, angiotensin II keeps the glomerulus filtering by constricting the efferent vessel to preserve the filtration gradient. Give an ACEi and GFR collapses, precipitating AKI.

Step 5 — Aldosterone

Aldosterone is a mineralocorticoid synthesised in the zona glomerulosa of the adrenal cortex. It binds intracellular mineralocorticoid receptors in the principal cells of the distal convoluted tubule and collecting duct, upregulating:

- ENaC (epithelial Na⁺ channel) — Na⁺ reabsorption

- ROMK channels — K⁺ secretion

- H⁺-ATPase in intercalated cells — H⁺ secretion

Net effect: Na⁺ in, K⁺ and H⁺ out. Hence the classic hyperaldosteronism triad — HTN, hypokalaemia, metabolic alkalosis.

👩‍⚕️ Adrenal cortex mnemonic: GFR = Salt, Sugar, Sex. Glomerulosa (aldosterone), Fasciculata (cortisol), Reticularis (androgens). Outer to inner.

ADH — the parallel volume-saving hormone

Angiotensin II stimulates ADH release from the posterior pituitary. ADH inserts aquaporin-2 into collecting duct principal cells, reabsorbing free water. Aldosterone retains isotonic saline; ADH retains pure water — together they restore both volume and pressure.

Clinical pharmacology

Drug class	Example	Mechanism	Key adverse effect
ACE inhibitors	Ramipril, lisinopril (-pril)	Block ACE	Dry cough (bradykinin), hyperkalaemia, angioedema, AKI in RAS
Angiotensin receptor blockers	Losartan, candesartan (-sartan)	Block AT1 receptor	Hyperkalaemia (no cough — bradykinin unaffected)
Aldosterone antagonists	Spironolactone, eplerenone	Block mineralocorticoid receptor	Hyperkalaemia, gynaecomastia (spironolactone only)
Direct renin inhibitor	Aliskiren	Blocks renin	Hyperkalaemia (rarely used)

> Pearl: Spironolactone is non-selective and also blocks androgen receptors — hence gynaecomastia and impotence. Eplerenone is selective for the mineralocorticoid receptor and is preferred when this is a problem.

Pathology corner

Primary hyperaldosteronism (Conn's) — autonomous aldosterone from an adrenal adenoma or bilateral hyperplasia. HTN, hypokalaemia, metabolic alkalosis, suppressed renin. Screen with aldosterone:renin ratio.

Secondary hyperaldosteronism — driven by a stimulus outside the adrenal. Renal artery stenosis is the classic cause: ↓ renal perfusion → renin ↑ → AT-II ↑ → aldosterone ↑. Renin is high. Suspect in young resistant HTN or older patients with flash pulmonary oedema and an abdominal bruit.

A sudden creatinine rise after starting an ACEi should prompt investigation for bilateral RAS.

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Test yourself

Which substance increases in haemorrhage?

• ((Insulin::No role in the acute response to hypovolaemia.))
• ((Plasma proteins::Concentration may rise with haemoconcentration but no active hormonal increase.))
• ((Angiotensin II::☑️ Hypovolaemia activates RAAS within seconds via JG cell baroreceptors and sympathetic drive.))
• ((Thrombin::Coagulation cascade — not part of the volume response.))
• ((Atrial natriuretic peptide::ANP falls in haemorrhage because atrial stretch is reduced.))

👩‍⚕️ ANP and angiotensin II move in opposite directions — a classic SBA pairing.

Which part of the kidney produces erythropoietin?

• ((Interstitial fibroblasts::☑️ Peritubular cortical fibroblasts sense hypoxia via HIF and secrete EPO.))
• ((Mesangial cells::Provide glomerular structural support; no EPO role.))
• ((Podocytes::Form the filtration slit diaphragm.))
• ((Macula densa cells::Sense distal tubular Na⁺ for tubuloglomerular feedback.))
• ((Proximal tubular epithelium::Reabsorbs filtrate; activates vitamin D but not EPO.))

What is the first substance released in response to hypotension?

• ((Renin::☑️ JG cells fire first — baroreceptor, macula densa and β1 sympathetic input all converge on renin.))
• ((Aldosterone::Downstream — needs angiotensin II to stimulate the zona glomerulosa.))
• ((ADH::Released later, driven partly by angiotensin II and osmoreceptors.))
• ((Angiotensin II::Cannot form until renin has acted on angiotensinogen.))
• ((Adrenaline::Sympathetic surge is fast but renin is the first RAAS component.))

What is the correct hormonal sequence in hypotension?

• ((Renin ↑ → Aldosterone ↑ → ADH ↑::☑️ Renin initiates; angiotensin II then drives aldosterone and ADH release.))
• ((ADH ↑ → Renin ↑ → Aldosterone ↑::ADH is not the initiating hormone of RAAS.))
• ((Aldosterone ↑ → Renin ↑ → ADH ↑::Aldosterone is downstream of renin, not the trigger.))
• ((Angiotensin II ↑ → Renin ↑ → ADH ↑::Angiotensin II cannot form before renin acts.))
• ((ADH ↑ → Aldosterone ↑ → Renin ↑::Reverses the physiological cascade.))

What has the most direct effect on blood volume after 1L blood loss?

• ((Renin::An enzyme — no direct vascular or tubular action itself.))
• ((Angiotensin II::☑️ Instant vasoconstriction plus aldosterone, ADH and thirst — the multifactorial effector.))
• ((Aldosterone::Important but acts over hours via gene transcription.))
• ((ADH::Retains free water; lacks the vasoconstrictor punch of angiotensin II.))
• ((Erythropoietin::Restores red cell mass over days to weeks, not acutely.))

What maintains vascular tone?

• ((Renin::Enzymatic cleavage only — no direct vascular effect.))
• ((Angiotensin I::Biologically inert precursor.))
• ((Angiotensin II::☑️ Potent AT1-mediated vasoconstriction of arteriolar smooth muscle.))
• ((Aldosterone::Acts on renal tubules, not directly on vessels.))
• ((ANP::Opposes RAAS — vasodilator and natriuretic.))

On which part of the nephron does aldosterone act?

• ((Proximal convoluted tubule::Bulk Na⁺ reabsorption but not aldosterone-dependent.))
• ((Loop of Henle::Countercurrent multiplier; aldosterone has no effect here.))
• ((Distal tubule and collecting duct::☑️ Aldosterone upregulates ENaC and ROMK in principal cells — Na⁺ in, K⁺ out.))
• ((Glomerulus::Filtration site, not a reabsorptive target.))
• ((Thin ascending limb::Passively permeable; no active aldosterone-driven transport.))

What enzyme converts angiotensin I to angiotensin II?

• ((Renin::Acts upstream — angiotensinogen to angiotensin I.))
• ((ACE::☑️ Membrane-bound zinc metallopeptidase, predominantly on pulmonary endothelium.))
• ((Chymase::Tissue alternative pathway — not the primary route tested.))
• ((Pepsin::Gastric protease, irrelevant.))
• ((Aminopeptidase::Degrades angiotensin II to angiotensin III.))

What is a recognised side effect of ACE inhibitors?

• ((Hypokalaemia::Wrong direction — ACEi cause hyperkalaemia via reduced aldosterone.))
• ((Dry cough::☑️ Bradykinin accumulates because ACE normally degrades it.))
• ((Peripheral oedema::Classic adverse effect of dihydropyridine calcium channel blockers.))
• ((Tachycardia::Not typical; ACEi tend to be neutral or slightly bradycardic.))
• ((Hypernatraemia::ACEi reduce Na⁺ retention, not increase it.))

👩‍⚕️ If a patient cannot tolerate the ACEi cough, swap to an ARB — same haemodynamics, no bradykinin effect.

Which zone of the adrenal cortex produces aldosterone?

• ((Zona glomerulosa::☑️ Outermost cortical layer — mineralocorticoids.))
• ((Zona fasciculata::Middle zone — cortisol.))
• ((Zona reticularis::Innermost zone — androgens (DHEA).))
• ((Adrenal medulla::Catecholamines from chromaffin cells.))
• ((Zona intermedia::Not a real adrenal layer.))

A 45-year-old with resistant hypertension has K⁺ 2.9, HCO₃⁻ 32, and suppressed plasma renin. Most likely diagnosis?

• ((Conn's syndrome::☑️ Primary hyperaldosteronism — autonomous aldosterone, low renin, hypokalaemic metabolic alkalosis.))
• ((Renal artery stenosis::Would give high renin (secondary hyperaldosteronism).))
• ((Phaeochromocytoma::Catecholamine excess — paroxysmal HTN, sweating, palpitations, not hypokalaemia.))
• ((Cushing's syndrome::Cortisol excess — central obesity, striae; K⁺ usually normal.))
• ((Addison's disease::Adrenal insufficiency — hypotension, hyperkalaemia, hyponatraemia.))

A patient with bilateral renal artery stenosis is started on ramipril. Creatinine doubles in a week. Why?

• ((Loss of angiotensin II-mediated efferent arteriolar constriction::☑️ Efferent tone was maintaining GFR; blocking it collapses the filtration gradient.))
• ((Direct nephrotoxicity of ramipril::ACEi are not directly nephrotoxic.))
• ((Acute interstitial nephritis::Possible but rare and not the mechanism here.))
• ((Rhabdomyolysis::Unrelated to ACEi initiation.))
• ((Contrast nephropathy::No contrast given in this scenario.))

A man on long-term spironolactone for heart failure complains of breast tenderness. Best alternative?

• ((Eplerenone::☑️ Selective mineralocorticoid receptor antagonist — no androgen receptor effect, no gynaecomastia.))
• ((Amiloride::ENaC blocker — K⁺-sparing but not a mineralocorticoid antagonist; weaker prognostic data in HF.))
• ((Furosemide::Loop diuretic — does not replace mineralocorticoid blockade.))
• ((Bendroflumethiazide::Worsens hypokalaemia; not equivalent.))
• ((Stop diuretics altogether::Mineralocorticoid blockade improves HF mortality — should not simply be discontinued.))

Revision summary

- ➡ Renin — JG cells of the afferent arteriole; triggered by low BP, low macula densa Na⁺, β1 sympathetic stimulation.

- ➡ Angiotensinogen made by the liver; cleaved to angiotensin I by renin.

- ➡ ACE (pulmonary endothelium) converts AT-I to AT-II; also degrades bradykinin (→ ACEi cough).

- ➡ Angiotensin II — vasoconstriction, aldosterone, ADH, thirst, sympathetic potentiation, PCT Na⁺ reabsorption, efferent arteriolar constriction (preserves GFR).

- ➡ Aldosterone — zona glomerulosa; acts on DCT/CD principal cells → Na⁺ in, K⁺ and H⁺ out.

- ➡ ACEi (-pril): cough, hyperkalaemia, angioedema, AKI in bilateral RAS.

- ➡ ARB (-sartan): same effects without the cough.

- ➡ Spironolactone → gynaecomastia; eplerenone is selective.

- ➡ Conn's = primary hyperaldosteronism → HTN, low K⁺, metabolic alkalosis, suppressed renin.

- ➡ Renal artery stenosis = secondary hyperaldosteronism, high renin; ACEi precipitates AKI.

- ➡ Adrenal cortex: GFR — Salt, Sugar, Sex.