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4. Physiology and pathophysiology > RAAS > Flashcards

RAAS Flashcards

1
Q

What is the main role of RAAS

A

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

  • Various components of RAAS can be found in brain, myocardium, vasculature, adrenal gland, kidney
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2
Q

Describe RAAS cascade

A

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 ¢
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3
Q

Control of renin secretion

A

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

o Inhibited by negative feedback from Ang II

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4
Q

Effects of ACE

A

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

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5
Q

Activation triggers RAAS

A
  • ↓ blood volume/CO => decr renal blood flow
  • ↓ [Na+]
  • β1 stimulation
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6
Q

Effects of RAAS

A
  • 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
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7
Q

Ang II actions

A
  • 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
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8
Q

Ang II: effect of aldosterone release

A

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

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8
Q

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

A

incr Na+ reabs

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9
Q

Ang II: effect of ADH secretion

A

incr H2O reabs

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10
Q

Ang II: effect of vasoconstriction of efferent arteriole

A

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.

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11
Q

Ang II: effect of facilitating symp syst

A

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

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12
Q

Ang II: effect on baroR

A

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

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13
Q

Ang II: effect of vasoconstriction

A

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

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14
Q

Ang II: effect of cardiac remodeling

A

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

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15
Q

Site of action of Ang II

A

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

16
Q

Role of ACE 2

A
  • Convert Ang II => Ang 1-7
  • Act on vascular R => inhibit vasoconstriction + Na+ retention
17
Q

Ang II R types

A
  • 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

18
Q

Intracell signaling when binding Ang II R

A
  • 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
19
Q

RAAS w/ systemic hypertension

A

Excess vasoconstriction partially mediated by Ang II

20
Q

RAAS in CHF

A
  • 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
21
Q

Site of action ACEi

A
  • Bind the same site of ACE on Ang I → block conversion to Ang II
22
Q

MOA ACEi

A

 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

23
Q

Major indications for ACEi

A

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

24
Q

Side effects ACEi

A

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

25
Q

Ci ACEi

A

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

26
Q

ACEi

A
  • Enalapril, benzepril, captopril, fosinopril
27
Q

MOA ARB

A

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

28
Q

ACEi and ARB in CHF

A

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

29
Q

ARB

A
  • Losartan, candesartan, telmisartan, valsartan
30
Q

Aldosterone antagonist MOA

A
  • 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
31
Q

Aldosterone antagonist

A
  • Spironolactone, eplerenon
32
Q

Aldosterone antagonist side effects

A

o HyperK: closely monitor

33
Q

Negative effects of aldosterone excess

A

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

34
Q

Vasodilators

A

Amlodipine
Hydralazine

35
Q

MOA amlodipine

A

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

36
Q

MOA hydralazine

A

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

37
Q

Side effects hydralazine

A

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

4. Physiology and pathophysiology (18 decks)

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