RAAS

Question 1

What is the main role of RAAS

Answer 1

Blood volume regulation
* Kidneys: dominant organ in blood volume control

• Various components of RAAS can be found in brain, myocardium, vasculature, adrenal gland, kidney

Question 2

Describe RAAS cascade

Answer 2

renin => secreted in granular ¢ of juxtaglomerular apparatus

• Renin = protease acting on angiotensinogen in liver => conversion to Ang I
  o Ang I => cleaved to Ang II in lungs
   By angiotensin converting enzyme = produced by vascular endothelial ¢

Question 3

Control of renin secretion

Answer 3

 Composition of tubular fluid in macula densa
 symmp stimulation
 BaroR in afferent arterioles
 Prostaglandins

o Inhibited by negative feedback from Ang II

Question 4

Effects of ACE

Answer 4

inactivates bradykinin (potent vasodilator)
 Majority of ACE in tissue, only 10% in circulation

Question 5

Activation triggers RAAS

Answer 5

• ↓ blood volume/CO => decr renal blood flow
• ↓ [Na+]
• β1 stimulation

Question 6

Effects of RAAS

Answer 6

• decr blood volume => compensatory Ang II mediated vasoconstriction => incr BP
• decr renal blood flow → decr afferent arteriole pressure + incr symp stimulation + decr Na+ flux by macula densa → incr renin release => incr Ang II

Question 7

Ang II actions

Answer 7

• incr aldosterone secretion
• Stim Na+/H+ exch on prox renal tubule
• incr ADH secretion
• vasoconstriction of efferent arteriole
• Stim thirst and salt appetite
• facilitate symp system
• reset baroR
• vasocontriction of arterioles
• cardiac remodeling

Question 8

Ang II: effect of aldosterone release

Answer 8

Adrenal cortex

o incr Na+ reabs. and K+ secretion in distal/collecting tubule => inhibit Na+/K+ pump
o incr H2O reabsorption => incr plasma volume
o *Secretion also stimulated by ↑K+ and ACTH

Question 8

Ang II: effect of Na+/H+ exch stimulation

Answer 8

incr Na+ reabs

Question 9

Ang II: effect of ADH secretion

Answer 9

incr H2O reabs

Question 10

Ang II: effect of vasoconstriction of efferent arteriole

Answer 10

incr glomerular pressure => filtration
o incr stimulation cause vasoconstriction of afferent arteriole => decr GFR => icnr creat/BUN
o Ang II will help maintain normal GFR but total renal blood flow is decr
o incr Filtration fraction => blood dehydration in efferent arteriole
 Hyperosmolality => incr oncotic + decr hydrostatic pressure
 Stimulate fluid reabsorption => incr blood vol.

Question 11

Ang II: effect of facilitating symp syst

Answer 11

o Promote central adrenergic activation in brainstem
o Facilitate neurotransmission in autonomic ganglia
o incr NE release, decr reuptake in symp nerve terminal

Question 12

Ang II: effect on baroR

Answer 12

act on central R AT1 =>
o decr hypertension associated bradycardia

Question 13

Ang II: effect of vasoconstriction

Answer 13

o incr intra¢ [Ca2+] via AT1 R
o Promote NE release => A1 R
o Stimulate ET1 release

Question 14

Ang II: effect of cardiac remodeling

Answer 14

Gq → activation of mitogen actiated prot kin (MAPKs)
o Myocardial hypertrophy
o Detrimental vascular and ventricular remodeling

Question 15

Site of action of Ang II

Answer 15

Vascular SM
Renal efferent arteriole
Prox renal tubule
Adrenal cortex
Central adrenergic activation
Ganglionic facilitation
Presyn R
Baroreflexes

Question 16

Role of ACE 2

Answer 16

• Convert Ang II => Ang 1-7
• Act on vascular R => inhibit vasoconstriction + Na+ retention

Question 17

Ang II R types

Answer 17

• 2 R subtypes: present in heart and vascular SM¢

o Heart: AT1/AT2 ratio = 2:1

o AT1: mediate adverse effects on heart and circulation
 incr vasoconstriction
 + inotropic effect
 incr growth/death rates of cardiomyo¢
* Arteriolar narrowing + myocardial hypertrophy
 Fibrosis
 incr Na+ retention
 Baroreflex reset: decr bradycardia during hypertension

o AT2:
 Late fetal phase: inhibition of growth, proapoptotic
 Heart disease: vasodilatory, protective

Question 18

Intracell signaling when binding Ang II R

Answer 18

• Ang II bind to AT1 => GTP binding protein Gq => phospholipase C
  o Gq: 3 subunits (A, B, sig)
  o Phospholipase C => membrane bound enzyme => formation of
   IP3 (inositol triphosphate) => SR => liberate Ca2+
• Promote Ca2+ dependent growth pathways
   DAG (diacyglycerol ) => activate protein kinase C (PKC)
• Activate MAP kinase => role in growth regulation + preconditioning
• Degree of activation determine signaling effect
  o Low: long term cardioprotective effect w/o hypertrophy
  o Medium: lead to hypertrophy w/o failure
  o High: hypertorphy + fibrosis and heart failure

Question 19

RAAS w/ systemic hypertension

Answer 19

Excess vasoconstriction partially mediated by Ang II

Question 20

RAAS in CHF

Answer 20

• Diastolic failure: decr emptying of LA/filling of LV => incr venous pressures + pulmonary congestion
• Systolic failure: decr SV + CO => decr peripheral perfusion
• Neurohumoral changes => incr SVR => incr afterload
  o symp activation +RAAS activation
  o Fluid retention => incr preload
  o incr circulating/tissue [Ang II]
   Vasoconstriction
   incr symp activation
   incr aldosterone => promote cardiac fibrosis + endothelial dysfct
  o Tissue renin angiotensin system:
   Activated during chronic CHF => mechanical deformity from incr LV pressure
• Blood volume >25-30% in severe CHF → incr diatolic ventricular pressures => congestion

Question 21

Site of action ACEi

Answer 21

• Bind the same site of ACE on Ang I → block conversion to Ang II

Question 22

MOA ACEi

Answer 22

 Ang II formation
o Arteriolar + venous dilation
 ↓ afterload and preload
 ↓ myocardial wall stress

o decr plasma [aldosterone] => incr Na+/H2O secretion
 Aldosterone escape phenomenon: do not remain fully blocked with chronic administration
o Indirect natriuretic + K+ retaining effects
o decr myocardial fibrosis/remodeling
o Mediate breakdown of bradykinin => decr degradation
 Bradykinin normally inactivated by kininase I and II
* Kininase II identical to ACE => ACEi lead to incr bradykinin
* Bradykinin act on endothelial ¢ => promotes release of NO + prostacyclin/PGE2

Question 23

Major indications for ACEi

Answer 23

o CHF
o Hypertension
o Acute/chronic MI
o Renoprotection
o Diabetic nephropathy
o Cardiovascular protection

Question 24

Side effects ACEi

Answer 24

o Cough (not reported in dogs)  2nd to incr sensitivity of cough reflex  incr formation of bradykinin + PG may play a role o Hypotension => orthostatic symptoms o HypoNa, hyperK o Renal failure: decr GFR  Underlying renal disease: 20%> in creatinine after starting ACEi o Angioedema: 2nd to bradykinin o Neutropenia: 2nd to captopril

Question 25

Ci ACEi

Answer 25

o Bilateral renal artery stenosis o Allergy/hypersensitivity o HyperK o High renal values

Question 26

ACEi

Answer 26

* Enalapril, benzepril, captopril, fosinopril

Question 27

MOA ARB

Answer 27

Angiotensin II receptor antagonist (ARB) * Block Ang II action on AT1 R o Avoid bradykinin accumulation → not affecting ACE  Reduce side effect vs ACEi (cough, angioedema) o AT2 is not blocked: potentially beneficial effect in CHF * Similar indications and contraindications as ACEi

Question 28

ACEi and ARB in CHF

Answer 28

o Associated w improved outcomes and cardiovascular protection o May allow better neurhormonal control due to series of blocking

Question 29

ARB

Answer 29

* Losartan, candesartan, telmisartan, valsartan

Question 30

Aldosterone antagonist MOA

Answer 30

* Bind aldosterone sites on distal tubule o decr myocardial fibrosis o decr release of cardiac NE => vasodilation  decr arrhythmia, sudden death o incr diuresis o ↓ aldosterone escape when combined to ACEi

Question 31

Aldosterone antagonist

Answer 31

* Spironolactone, eplerenon

Question 32

Aldosterone antagonist side effects

Answer 32

o HyperK: closely monitor

Question 33

Negative effects of aldosterone excess

Answer 33

o incr myocardial fibrosis o Worsen CHF o Arrhythmias (NE) o Inhibition of NO release o incr response to vasconstrictors (Ang)

Question 34

Vasodilators

Answer 34

Amlodipine Hydralazine

Question 35

MOA amlodipine

Answer 35

o Dihydropyridine vasoselective Ca2+antagonist of SM¢ in systemic asrterioles

Question 36

MOA hydralazine

Answer 36

o Potent arteriolar dilator, no venous tone effects → ↓ afterload  incr prostacyclin => SM¢ relaxation * decr vascular resistance in renal/coronary/cerebral/mesenteric beds > skeletal muscles o incr aortic compliance o incr myocardial contractility  Histamine release => NE release

Question 37

Side effects hydralazine

Answer 37

activation of baroR → ↑ rebound renin release → ↑ Ang II and aldosterone