L44: RAAS System

Question 1

Regulation of blood pressure

Answer 1

Long term regulation: control blood volume —> ECF volume + BP regulation

• Neural: immediate, local, disappear immediately
• Hormonal: slower, global, persist for hours
• Neural-hormonal: rapid onset, global, long-lasting

1. regulation of water excretion
   —> GFR kept CONSTANT
   —> alter reabsoption of water by vasopressin (ADH)
   —> regulate body fluid osmolarity
2. regulation of salt excretion
   —> RAAS system —> aldosterone
   —> ANP (atrial natriuretic peptide)

Question 2

Neural control of BP

Answer 2

Principal site: Atria volume receptors (stretch receptors)

• junction of VC with R atrium + Pulmonary vein with L atrium
• ↑ blood volume —> ↑ venous pressure —> ↑ venous return —> ↑ atrial filling —> ↑ stretch of wall —> ↑ atrial receptor activation

Reflex response:
1. ↑ R cardiac sympathetic nerve (atria and nodal tissue) —> ↑ HR —> ↓ SV (CO remain unchanged) —> protects atria from overstretch

2. ↓ Renal sympathetic nerve —> afferent arteriole vasodilation —> ↑ glomerular capillary pressure —> ↑ GFR —> ↑ urine formation —> ↓ blood volume
3. ↓ skeletal muscle + splanchnic circulation sympathetic nerve —> vasodilation —> ↓ TPR —> ↓ BP from large volume

Question 3

***Neurohormonal control of BP by RAAS system

Answer 3

1. Atrial volume receptors (ADH release):
   - ↑ Blood volume —> afferent signal to CNS —> ↓ ADH release from hypothalamus + pituitary gland —> ↓ water reabsorption —> ↑ urine volume —> ↓ Blood volume
2. RAAS system (Renin release):
   Angiotensinogen (inactive precursor in blood) —Renin(proteolytic enzyme)—> Angiotensin I —(ACE in pulmonary endothelial cells)—> Angiotensin II (active form)

Renin release at cellular level: controlled by ↑ intracellular cAMP (inhibited by ↑ intracellular Ca)

1. Juxtaglomerular cells (baroreceptors in afferent arteriole)
   - ↑ afferent arteriole BP —> ↑ JG cell stretch —> ↑ depolarisation of JG cell —> Ca entry —> ↑ intracellular Ca —> ↓ renin release
2. Changes in GFR (LOCAL EFFECT ONLY) (should be kept constant) (Tubulo-glomerular feedback: GFR control NaCl delivery to Macula densa in distal tubule in JG appartus)
   - ↑ Blood flow —> ↑ GFR —> ↑ NaCl reabsorption at macula densa (NaK2Cl cotransporter) —> ↑ intracellular Na —> ↑ ATP break down to adenosine by Na/K-ATPase —> ↑ adenosine —> afferent arteriole vasoconstriction —> ↓ glomerular capillary pressure —> ↓ GFR
   - ↓ Blood flow —> ↓ GFR —> ↓ NaCl reabsorption at macula densa (NaK2Cl cotransporter) —> ↓ intracellular Na —> activation of COX2 + PGE2 synthase —> PGE2 release from Macula densa —> act on JG cell —> ↑ intracellular cAMP —> ↑ renin release —> ↑ angiotensin II —> efferent arteriole vasoconstriction —> ↑ glomerular capillary pressure —> ↑ GFR
3. Renal sympathetic nerve activation
   - ↑ NE / circulating catecholamine —> β1 receptor of JG cell —> ↑ intracellular cAMP —> ↑ renin release
4. Prostaglandin (esp Prostacyclin)
   - PGE2, PGI2 —> JG cell —> ↑ intracellular cAMP —> ↑ renin release

Question 4

***Actions of Angiotensin II

Answer 4

1. Vasoconstrictor effect
   - mainly affect renal vessels at normal concentration
   —> efferent arteriole > afferent arteriole vasoconstriction
   —> keep GFR CONSTANT during ↓ renal blood flow due to ↓ BP

• ↓ BP —> high concentration angiotensin —> widespread vasoconstriction in body
  —> also ↑ TPR and ↑ BP

2. Salt reabsorption
   - ↑ activity of Na-transport protein
   - apical membrane: Na/H exchanger (proximal + LoH + distal) + epithelial Na Channel (distal + collecting duct)
   - basolateral membrane: Na/HCO3 cotransporter (proximal)+ Na/K-ATPase (ALL)
3. Circumventricular organs (Area Postrema, Subfornical Organ, Organum Vasculosum)
   - 3 areas send signals to other areas of brain
   —> ↑ BP, ↑ thirst, ↑ salt appetite, ↑ ADH release
4. ↑ Aldosterone release (mineralocorticoid)
   - synthesised in adrenal cortex, release also stimulated by ↑ ECF [K]
   - ↑ aldosterone —> ↑ Na/K pump activity at distal tubule basolateral membrane —> ↑ Na, ↓ K in tubular cell —> ↑ concentration gradient of both ions
   —> ↑ Na reabsorption from filtrate, ↑ K excretion into filtrate

Question 5

Intra-renal and Intra-cranial RAAS system

Answer 5

Intra-renal:
Angiotensinogen: proximal tubule
Renin: JG cells
ACE: proximal tubule (systemic: pulmonary endothelial cells)
Angiotensin II receptor: throughout kidney
—> Angiotensin II can be formed locally within kidney without travelling in bloodstream

Intra-cranial:
- All components expressed in the brain:
Angiotensinogen, renin, ACE, Angiotensin receptor
- kept separate from systemic RAAS due to BBB
- high density of Angiotensin I receptor
- for CV regulation
1. ↑ sympathetic activity
2. Baroreflex sensitivity modulation
3. ↑ ADH release
4. ↑ thirst

• ↑ Blood volume —> ↓ renin —> ↓ angiotensin —> ↓ aldosterone —> ↓ salt and water reabsorption —> ↑ loss of salt and water —> ↓ blood volume

Question 6

Salt retention in heart failure

Answer 6

Low CO —> ↑ TPR —> ↓ renal blood flow —> ↓ GFR —> ↑ renin release —> ↑ angiotensin —> ↑ aldosterone —> ↑ salt and water reabsorption —> salt and fluid overload —> further exacerbate heart failure

*** even though salt and fluid retention is undesirable in heart failure, but GFR is sensed by kidney itself

Question 7

***Hormonal response to increased blood volume

Answer 7

Atrial Natriuretic Peptide (ANP) —> ***Natriuresis

• secretory granules from atrial muscle cells
• ↑ blood volume —> stretch of atrial muscle —> ↑ release of ANP —> enter blood travel to kidney

1. ↓ Na reabsorption (Natriuresis)
   - inhibit Na/H exchanger by angiotensin II action (proximal strongly affected, LoH, distal less affected) —> ↓ Na reabsorption (Natriuresis) —> ↓ water reabsorption
   - inhibit epithelial Na channel (by ↑ cGMP then phosphorylation)—> ↓ Na reabsorption (Natriuresis) —> ↓ water reabsorption
2. ↑ GFR
   - Afferent arteriole vasodilation —> ↑ glomerular capillary pressure —> ↑ GFR
3. inhibit ADH effects
   - ↓ insertion of Aquaporins into collecting duct cell membrane —> ↓ water reabsorption —> diuresis
4. ↓ renin release

B-type Natriuretic Peptide (ANP)

• secreted by ventricles instead of atrium
• similar effects but 10x lower affinity —> less effective