• Sites of Action:
  • vascular smooth muscle
  • brain
  • kidney
  • adrenal cortex

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• Renin-angiotensin System Physiology:
  • arterial blood pressure regulation
  • fluid and electrolyte balance regulation

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• Blood Pressure/Cardiovascular Effects: Angiotensin II
  • Properties:
    • Very potent vasopressor (40 times more potent than norepinephrine)
    • Following IV administration, rapid pressor effect
    • Vasopressor response: Mechanisms of Action
      • Direct arteriolar smooth muscle contraction
      • CNS-mediated
      • ANS-mediated
    • Minimal reflex bradycardia (angiotensin II CNS action resets baroreceptor reflex system, making it less sensitive)

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• Autonomic Effects:
  • stimulates autonomic ganglia
    • promoting release of epinephrine and norepinephrine
    • enhances adrenergic nerve terminal neurotransmission
      • increases norepinephrine release; reduces norepinephrine re-uptake
• Slight inotropic cardiac effect

• Adrenal Cortical Effects:
  • Angiotensin II:
    • acts on zona glomerulosa, increasing aldosterone synthesis
    • (higher doses) -- increases glucocorticoid synthesis

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• Renal Effects:
  • Angiotensin II:
    • Renovascular constriction
    • enhanced sodium reabsorption at proximal tubule
    • inhibition of renin secretion

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• CNS Effects:
  • Angiotensin II:
    • central blood-pressure effects
    • stimulates drinking (dipsogenic effect)
    • stimulates vasopressin and ACTH secretion
• Cell Growth--Angiotensin II:
  • Vascular and cardiac muscle cell mitogen
    • may cause myocardial hypertrophy
    • Angiotensin converting enzyme inhibitors may reduce or prevent morphological changes following myocardial infarction (remodeling) -- which may lead to cardiac failure (CHF)

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• Angiotensin Receptors:
  • Overview
    • Angiotensin II receptors -- widely distributed
    • plasma membrane localization-- rapid onset of effects
    • At least two major receptor subtypes:
      •   AT₁ -- high losartin affinity
        • equal affinity for saralasin and angiotensin II
        • predominates at vascular smooth muscle
        •   vascular smooth muscle: G- protein coupled system
          • receptor activation at vascular smooth muscle:
            1. phospholipase C -mediated production of inositol triphosphate IP₃ and diacylglycerol (DAG)
               • Activation of IP₃, DAG cascade: DAG may activate smooth muscle Ca²⁺ channels; IP₃ releases Ca²⁺ from endoplasmic and sarcoplasmic reticulum
            2. smooth muscle contraction
        • non-G protein coupled system at other sites
      •   AT₂ -- low losartin affinity
        • equal affinity for saralasin and angiotensin II

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