Renin-Angiotensin System

Question 1

Describe the Steps of the Renin Angiotensin System

Answer 1

1. Angiotensionegen → Angiotensin I (Renin)
2. Angiotensin I → Angiotensin II (ACE)
3. Angiotensin II binds Angiotensin II receptors
4. Angiotensin II receptors cause release of Aldosterone
5. Blood Pressure Regulation

Question 2

Juxtaglomerular apparatus (macula densa, sympathetic nerves)

Answer 2

Renin containing cells

• Macula Densa - specialized epithelial cell
• Sympathetic nerves - Afferent arteriole

Question 3

3 Primary mechanisms of Renin release

Answer 3

1. Intrarenal baroreceptor - stretch/renal perfusion pressure (decreased pressure increase renin)
2. Macula densa - sodium load (decrease salt increase renin)
3. β-adrenergic receptor - Sympathetic nerves (If blocked, decrease renin)

Question 4

Angiotensin II effect on Renin release

Answer 4

• Angiotensin II causes feedback inhibition
• Suppresses renin release by direct action on JG cells

Question 5

Different roles of Angiotensin receptors (AT₁)

Answer 5

AT₁

• Vasoconstriction
• Vascular proliferation
• Aldosterone secretion
• Cardiac myocyte proliferation
• Increased sympathetic tone

Question 6

Different roles of Angiotensin receptors (AT₂)

Answer 6

AT₂

• Vasodilation
• Antiproliferation
• Apoptosis

Question 7

Mechanism of action for AT₁ receptor

Answer 7

• Angiotensin II binds AT₁
• Gq → PLC
• PLC → IP₃ and DAG
• IP₃ leads to release of Ca²⁺

Question 8

AT₁ receptor effects on vascular smooth muscle

Answer 8

• Arterial vasoconstrictor - increase BP
• Hypertrophy - increase in wall to lumen ratio
  
  • Increase extracellular matrix proteins such as collagen

Question 9

AT₂ receptor effects on vascular smooth muscle

Answer 9

• Endothelium-dependent vasodilation (NO mediated)
• Inhibition of proliferation of smooth muscle
• Promotes apoptosis

Question 10

How does the adrenal cortex promote sodium reabsorption

Answer 10

Stimulates aldosterone biosynthesis and secretion via AT₁ receptor

Question 11

Effects of aldosterone are blocked by ______ and ______

Answer 11

Spironolactone; Eplerenone

Question 12

Actions of Angiotensin on CNS

Answer 12

• Promotes thirst-dipsogenic
• Promotes ADH release
• Promotes positive water balance

Question 13

Angiotensin actions on Sympathetic Nervous System

Answer 13

• Facilitates norepinephrine release
• Inibits norepinephrine reuptake
• Promotes epinephrine secretion from adrenal medulla

Question 14

Angiotensin Actions on the Heart

Answer 14

• Hypertrophy of cardiac myocytes
• Increase in extracellular matrix production of fibroblasts

Question 15

Mechanism of action for Aldosterone

Answer 15

• Specific mineralcorticoid receptor agonist
• Activates expression of target genes involved in sodium reabsorption and potassium secretion

Question 16

Where in the kidney does Aldosterone act?

Answer 16

Principal cells of the collecting duct

Question 17

Aldosterone actions of Heart

Answer 17

• Fibrosis (both ventricles)
• Left ventricular hypertrophy

Question 18

Renin Angiotensin System pathology (Hypertension) - 2 methods

Answer 18

• Angiotensin II leads to:
  
  • vasoconstriction ⇒ increases BP
  • Aldosterone ⇒ increases BP

Question 19

Renin Angiotensin System Pathology (CHF)

Answer 19

• Vasoconstriction increases afterload
  
  • affects sympathetic nervous system
• Arrhythmia
• Promotes myocardial hypertrophy and apoptosis
• Aldosterone increases pre-load (fibrosis and LVH)

Question 20

Types of Renin Angiotensin System inhibitors

Answer 20

1. AT₁receptor blocker
2. ACE inhibitor
3. Renin inhibitor

Question 21

Losartan

Answer 21

Competitive angiotensin receptor antagonist - selective for AT₁

Question 22

Losartan

Adminstration:

Use:

Answer 22

Administration: Orally active

Use: Treatment of essential HTN

Question 23

Losartan - Reduction of Blood Pressure

Answer 23

Reduces blood pressure without increasing heart rate

• Should be used w/ caution in patients with volume depletion
• Diuretics enhance action
  
  • Renal failure may decrease in patients with CHF or renal artery stenosis

Question 24

Losartan - Improvement of HF

Answer 24

• Decreases BP (afterload)
• Reduces left ventricular filling pressure
• Decreases aldosterone - reduces sodium retention, fibrosis and hypertrophy (decreases preload)

Question 25

Losartan is contraindicated in \_\_\_\_\_\_ Side Effects:

Answer 25

Pregnancy Side Effects: Dizziness, cough, angiodema

Question 26

ACE inhibitors

Answer 26

1. Captopril 2. Enalapril 3. Lisinopril

Question 27

Direct action of ACE Inhibitors

Answer 27

* Block angiotensin II formation and bradykinin degradation

Question 28

ACE Inhibitors Administration: Use: Side Effects:

Answer 28

Administration: Orally active Use: Essential HTN related to renin activity Side Effects: rash, proteinuria, and neutropenia occur with captopril (cough and angiodema may occur)

Question 29

ACE Inhibitors - Reduction of BP

Answer 29

**Reduce BP without Increasing HR** * Should be used with caution in volume depleted patients * Diuretics enhance action

Question 30

ACE Inhibitors - Improvement of HF

Answer 30

* Decreases BP (Afterload) * Reduces left ventricular pressure * Increases cardiac output * Decreases aldosterone (Preload)

Question 31

Enalapril and lisinopril are \_\_\_\_\_\_\_\_

Answer 31

pro-drugs Enalapril → Enalaprilate (Active) Lisinopril → Lisinoprilate (Active)

Question 32

Aliskiren

Answer 32

Renin inhibitor

Question 33

Aliskiren Administration: T_1/2: Use:

Answer 33

Administration: Orally Active T_1/2: 24 hours - given once daily Use: Treat HTN (lowers BP with no change in HR)

Question 34

Aliskiren HTN effects

Answer 34

* HTN effects related to pretreatment plasma renin activity * Enhanced by Diuretic, ACE inhibitor or AT₁ blocker * Decrease plasma angiotensin II and aldosterone