U1vi: Physiology of RAAS

Definition

  • RAAS = an enzymatic cascade involved in the defence of ECF volume & maintenance of BP
RAAS
  • Renin secretion = rate limiting step
  • AII = main effector

Renin

  • Definition = peptide hormone
  • Synth + storage
    • From PRORENIN
    • Synthesised in Juxtaglomerular Granular Cells
    • Which are mainly located in medial tunica of aff. arteriole
    • Stored in vesicles
Renin
  • Release

↑ cAMP (stimulatory)

  • Catecholamines (β1 receptor)
  • PGI2 & E2
  • NO (inhib cAMP degradation via ↑GMP)
  • Milrinone (PDEI = ↑cAMP)

↑Ca2+ (inhibitory)

  • ↑Aff a. perfusion = ↑juxtaglom [Ca2+]
  • Control of release

↑ Renin

  • NO, PGI2, PGE2 = ↑renin (↑cAMP)
  • NA = β1 stimulation of β1 receptor in juxtaglom. Cells = ↑renin (↑cAMP)
  • Arterial P inverse relation to renin secretion
  • ↓pressure outside autoregulatory range for GFR = ↑renin
  • ↓[NaCl] = detected by Macula Densa = ↑renin
  • Metabolism: renin t½ ∝ 80min
  • Actions: it’s only function is to split ANGIOTENSINOGEN → AI

↓ Renin

  • AII → direct inhibition via AT1 receptor (↑Ca2+ = ↓Renin)

Ace

  • Enzyme of ENDOTHELIAL CELLS
  • Converts AI → AII by removing 2 α-acids
  • Most conversion occurs as blood passes through lungs
  • Also inactivates Bradykinin

Angiotensinogen

  • Synthesised by liver
  • ↑release stimulated by glucocorticoids, oestrogen, TH, AII

Angiotensin II

  • Definition: glycoprotein effector of RAAS
  • Synthesis: rate limiting step is renin ∴anything which ↑renin = ↑AT II formed by                
  • Metabolism: t½ 2 mins, metabolised by peptidases
  • Actions:
    • Agonist at Receptors AT1 & AT2 (GPR)
    • AT1
      • GPCR
      • Gq → phospholipase C → ↑Ca2+
    • AT2
      • GPCR
      • Opens K+ channel & ↑NO production
      • Abundant in foetal life → in adults, mostly concentrated to brain
    • AT1 receptors responsible for most actions
      • Vascular smooth m.
      • Adrenal cortex
      • Kidney
      • Brain

Vasc Smooth M

    • Strong pressor → ↑MAP

Adrenal Cortex

    • ↑Aldosterone secretion → ↑Na+ = ↑circulatory volume

Renal

    • Contraction of Mesangial cells → VC aff > eff = ↓GFR
    • ↑Na+ @ PT
    • ↓Renin secretion (because ↑ Ca2+ via AT1 receptor) = –ve feedback

NB: AII stimulates local release of Prostaglandins which antagonises renal VC

Brain

    • ↑ outflow → ↑MAP
    • Activates thirst centre → ↑circulatory volume
    • ↑ADH
    • ↑ACTH secretion
    • ↑Vasopressin production

Angiotensin III

  • 40% pressor activity of AII
  • 100% Aldosterone stimulating activity of AII

Aldosterone

  • Definition: the 1° MINERALOCORTICOID is a steroid hormone produced by Zona Glomerulosa
  • Synthesis:

Cholesterol

↓

Pregnenolone

↓

Progesterone

↓

Aldosterone

  • Cells of Adrenal Cortex do not store the hormones they secrete, they produce & release them on demand
  • Release: diurnal → more than 70% secreted between 0700 – 1000h
  • Control of release:
    • ↑AII ***
    • ↑K+
    • ↑ACTH → catalyses cholesterol → pregnenolone
    • ↑Atrial stretch
  • Metabolism
    • t½ 20 mins
    • Transported bound to proteins
    • 90% inactivated by single pass through liver
  • Actions
    • Binds intracellular receptors

→ ∆ DNA transcription

→ ↑Na/K/ATPase on BM of kidney, colon, bladder

Aldosterone Action in the Kidney

Principle Cells

    • 70% cells
    • Secrete K → depending on load:
    • Active transport via Na/K/ATPase

Aldosterone (+)

    • ↑Na+ reabs
    • ↑K+ excretion
    • Enhances absorption by promoting more Na/K/ATPase insertion on Basolateral Membrane
Aldosterone (+)

Type A Intercalated Cells

    • 30% cells
    • Reabsorbs K+
    • Active transport via K/H/ATPase
    • Because of Na/K exchange in Principle Cells
    • Lumen of Type A Intercalated cells has high [K+]
    • ↑H+/ATP activity
    • ∴not all K+ lost
      • H+ secreted → ALKALINE
      • Cl– for electroneutrality → HYPERCHLORAEMIA

Overall

  • ↑Na+ reabs → H2O follows → ↑circulatory volume
  • H+ loss → ALKALOSIS
  • ↑Cl – reabs → Hyperchloraemia