G7ii: Pathophysiological basis for using ACEi + ARB in HF
- RAAS = an enzymatic cascade involved in the defence of ECF volume & maintenance of BP
- RENIN secretion = rate limiting step
- AII = main effector
↓BP
↓
↓firing of BaroR
↓
↓ renal perfusion + ↑symp activity + ↓[NaCl] to macula densa
↓
↑RENIN secretion
↓
AII
↓
VC
Aldosterone secretion
Endothelin secretion
Thirst
↑ADH
↑NaCl
Myocyte hypertrophy
↓
Restores ECF & BP
However, in HF, RAAS activation is detrimental
↓myocardial contractility
↓
↓CO
↓
↑symp activity
↓
↑RENIN
↓
↑NaCl + H2O retention + symp activation
↓
↑PreL + ↑afterL
↓
Adverse ventricular remodelling
↓
Ventricle dilation + hypertrophy
↓
LV dysfunction
∴ACE inhibitors & angiotensin receptor blockers have been used to prevent the deleterious effects of RAAS activation
RAAS important → incorporates:
- Renal: control of renal haemodynamics + Na+ excretion
- CVS: BP regulation
- Endocrine: secretion of aldosterone
- Neuro: actions of angiotensin on brain + ANS

Rate on renin secretion is the primary rate controller for this system + ∴ the actions of AII
Renin
- A protease with t ½ 80 mins
- Synthesised as a prehormone PRORENIN → RENIN
- Synthesised + stored + released by juxtaglomerular cells
- The juxtaglomerular apparatus (aff, eff arterioles + macula densa) are innervated by SNS
Control of renin secretion
↑ RENIN Secretion
- ↓renal perfusion P
- ↓[NaCl] to macula densa
- Symp stimulation: β1 receptor on juxtaglom cells → GS → ↑AC → ↑cAMP → ↑RENIN
- Prostaglandins
↓ RENIN Secretion
- ↑renal perfusion P
- ↑[NaCl] to macula densa
- Angiotensin II (-ve feedback)
- Vasopressin (ADH)
Angiotensinogen
- Protein substrate for RENIN
- Synthesised in liver
- Production ↑with glucocorticoids, oestrogen, pregnancy
AI
- Little biological activity
AII = glycoprotein t ½ 2 mins = EFFECTOR of RAAS
- Vascular smooth m.
- Adrenal cortex
- Kidney
- Brain
- Acts on 2 receptors: AT1 & AT2
AT1 → mediates most actions
- GPCR
- Gq → ↑DAG + IP3 → ↑Ca2+ → smooth m. contraction
- Vascular smooth m.
- Potent VC → ↑MAP
- Adrenal cortex
- ↑aldosterone synthesis → ↑Na+ reabsorbed @ DCT
- Kidney
- VC aff > eff arterioles → ↓NFP
- ↑Na+ reabsorbed @ PT
- ↓RENIN secretion (-ve feedback)
- Brain
- ↑symp outflow → ↑MAP
- Stimulates thirst centre → ↑H2O uptake
- Stimulates hypothalamus → ↑ADH release from PPG
Acei & Renal Funtion
AII = VC efferent > afferent
- But eff diameter is smaller than aff. @ basal state
- ∴VC by AII ↑↑↑resistance
- To counteract:
→ AII stimulates NO release from aff.
→ AT2 receptor VD via CYP450
∴ When GFR is dependent on AII efferent tone (HF, renal a. stenosis) → ACE can induce renal failure
RBF, GFR, remain constant over wide pressure range
- ↓perfusion P
- Renal autoreg dilate aff a.
- RENIN released
- ↑AII = VC afferent art.
- Maintain filtration P
- ↓AII formation
- ↓efferent a. resistance
- ↓forces driving filtration
- ↓GFR
When RENIN is blocked, the entire renal mass is perfused at much lower P