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
Angiotensinogen

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