Lecture Notes: Physiology, Renin Angiotensin System

Introduction

• Renin-angiotensin-aldosterone system (RAAS)
  • Regulates blood volume, electrolyte balance, and vascular resistance.
  • Involves renin, angiotensin II, and aldosterone.
  • Responds to decreased renal blood pressure, salt delivery, and beta-agonism.
  • Expanded understanding due to newer discoveries.

Organ Systems Involved

• RAAS is involved in multiple organ systems:
  • Kidneys
  • Lungs
  • Systemic vasculature
  • Adrenal cortex
  • Brain

Function

• Mediates cardiac, vascular, and renal physiology by regulating:
  • Vascular tone
  • Salt and water homeostasis
• Role in hypertension, heart failure, cardiovascular, and renal diseases.
• Medications blocking RAAS improve outcomes.

Mechanism

Renin

• Produced in juxtaglomerular cells in kidneys.
• Activated by prorenin cleavage.
• Stimuli for release:
  1. Changes in renal perfusion
  2. Sodium and chloride delivery
  3. Increased beta-sympathetic flow
  4. Humoral factors (e.g., angiotensin I, potassium)
• Half-life: 10-15 minutes.

Angiotensinogen

• Secreted by the liver.
• Cleaved by renin to form angiotensin I.

Angiotensin I

• No known biological activity.

Angiotensin-Converting Enzyme (ACE)

• Expressed on endothelial cells, mainly in lungs.
• Converts angiotensin I to angiotensin II.

Angiotensin II

• Main mediator of RAAS effects:
  1. Vasoconstriction
  2. Aldosterone secretion
  3. Sodium reabsorption
  4. Increased sympathetic outflow
  5. Vasopressin release
• Implicated in hypertension, atherosclerosis, heart failure, kidney disease.

Angiotensin Receptors

• Type 1 (AT1-R):
  • Causes vasoconstriction, sodium reabsorption.
  • Pathogenic states: inflammation, fibrosis, oxidative stress.
• Type 2 (AT2-R):
  • Mediates vasodilation, natriuresis.
  • Opposes AT1-R effects.

Aldosterone

• Synthesized in adrenal cortex.
• Regulated by angiotensin II, ACTH, potassium.
• Mediates effects through mineralocorticoid receptors.
• Regulates sodium reabsorption, water homeostasis, and thirst.

Clinical Significance

• Overactivation of RAAS linked to cardiovascular and renal diseases.
• Implicated in primary and secondary hypertension.
• Medications targeting RAAS:
  • Direct Renin Inhibitors: Aliskiren
  • ACE Inhibitors: Lisinopril, Captopril, etc.
  • ARBs: Valsartan, Candesartan, etc.
  • MR Antagonists: Spironolactone, Eplerenone
  • Aldosterone Synthase Blockers: Baxdrostat
  • ENaC Blockers: Amiloride, Triamterene
• Improves renal perfusion, reduces inflammation, hypertrophy, fibrosis.