The Renin-Angiotensin-Aldosterone System (RAAS)

I. Introduction: Master Regulator of Blood Pressure

  • Complex, multi-organ endocrine cascade.
  • Fundamental for long-term regulation of arterial blood pressure, fluid volume, and sodium balance.
  • Dysregulation contributes to hypertension, heart failure, kidney disease.

II. Core Components

Component Type Source Primary Function
Angiotensinogen Pro-hormone Liver Precursor for cascade
Renin Enzyme Kidneys (JG Cells) Converts Angiotensinogen to Angiotensin I
Angiotensin I Peptide Circulation Weak, inactive intermediate
ACE Enzyme Lungs (Endothelium) Converts Angiotensin I to Angiotensin II
Angiotensin II Peptide Circulation Main effector (vasoconstrictor, stimulates Aldosterone/ADH)
Aldosterone Steroid Adrenal Gland Promotes Na⁺ and water reabsorption
ADH (Vasopressin) Peptide Posterior Pituitary Promotes water reabsorption

III. Activation Cascade

  • Stimulus: Low blood pressure, low NaCl in distal tubule, sympathetic nervous system stimulation.
  • Kidney (JG Cells): Release Renin.
  • Renin: Converts Angiotensinogen (from liver) to Angiotensin I.
  • ACE (Angiotensin-Converting Enzyme): Converts Angiotensin I to Angiotensin II.

IV. Powerful Effects of Angiotensin II

  • Potent Vasoconstriction: Increases systemic vascular resistance, raising blood pressure.
  • Stimulation of Aldosterone Release: From adrenal cortex, leading to Na⁺ and water reabsorption.
  • Stimulation of ADH Release: From posterior pituitary, leading to water reabsorption.
  • Direct Renal Effects: Constricts efferent arterioles, maintaining GFR.
  • Central Nervous System Effects: Stimulates thirst and salt appetite.

V. Roles of Aldosterone and ADH

  • Aldosterone (Salt-Retaining Hormone):
    • Acts on DCT and collecting duct.
    • Increases Na⁺ and water reabsorption, K⁺ and H⁺ excretion.
    • Increases blood volume and pressure.
  • ADH (Water-Retaining Hormone):
    • Acts on collecting duct.
    • Increases water reabsorption (via aquaporins).
    • Reclaims only water, independent of sodium.

VI. Counter-Current Mechanism

  • Function: Establishes and maintains the hypertonic medullary interstitial fluid, essential for concentrating urine.
  • Components:
    • Loop of Henle (Multiplier): Creates the osmotic gradient (descending limb permeable to water, ascending limb actively transports salt).
    • Vasa Recta (Exchanger): Preserves the gradient while supplying blood to the medulla.
  • Significance: Allows ADH to effectively reabsorb water from the collecting duct.

VII. Regulation and Negative Feedback

  • Upregulation (Activation): Low BP, low NaCl, sympathetic stimulation.
  • Downregulation (Inhibition):
    • High blood pressure directly inhibits renin.
    • Angiotensin II provides negative feedback on renin.
    • Atrial Natriuretic Peptide (ANP): Released by heart atria in response to high blood volume; counteracts RAAS by causing vasodilation, inhibiting renin/aldosterone, and promoting Na⁺/water excretion.

VIII. Pharmacological Intervention

Drug Class Examples Mechanism of Action
ACE Inhibitors Lisinopril Block ACE, preventing Angiotensin II formation
ARBs Losartan Block AT1 receptors, preventing Angiotensin II effects
Direct Renin Inhibitors Aliskiren Directly inhibit Renin
Aldosterone Antagonists Spironolactone Block aldosterone receptors

IX. Clinical Significance

  • Hypertension: Chronic overactivation of RAAS is a primary cause.
  • Heart Failure: RAAS activation initially compensatory, but chronic activation is detrimental (increases afterload, volume overload, cardiac remodeling).
  • Chronic Kidney Disease (CKD): RAAS activation contributes to progression (increases intraglomerular pressure, inflammation).
  • Myocardial Infarction (Heart Attack): RAAS activation contributes to adverse cardiac remodeling.