RAAS Flashcards
What is the main role of RAAS
Blood volume regulation
* Kidneys: dominant organ in blood volume control
- Various components of RAAS can be found in brain, myocardium, vasculature, adrenal gland, kidney
Describe RAAS cascade
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 ¢
Control of renin secretion
Composition of tubular fluid in macula densa
symmp stimulation
BaroR in afferent arterioles
Prostaglandins
o Inhibited by negative feedback from Ang II
Effects of ACE
inactivates bradykinin (potent vasodilator)
Majority of ACE in tissue, only 10% in circulation
Activation triggers RAAS
- ↓ blood volume/CO => decr renal blood flow
- ↓ [Na+]
- β1 stimulation
Effects of RAAS
- 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
Ang II actions
- 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
Ang II: effect of aldosterone release
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
Ang II: effect of Na+/H+ exch stimulation
incr Na+ reabs
Ang II: effect of ADH secretion
incr H2O reabs
Ang II: effect of vasoconstriction of efferent arteriole
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.
Ang II: effect of facilitating symp syst
o Promote central adrenergic activation in brainstem
o Facilitate neurotransmission in autonomic ganglia
o incr NE release, decr reuptake in symp nerve terminal
Ang II: effect on baroR
act on central R AT1 =>
o decr hypertension associated bradycardia
Ang II: effect of vasoconstriction
o incr intra¢ [Ca2+] via AT1 R
o Promote NE release => A1 R
o Stimulate ET1 release
Ang II: effect of cardiac remodeling
Gq → activation of mitogen actiated prot kin (MAPKs)
o Myocardial hypertrophy
o Detrimental vascular and ventricular remodeling
Site of action of Ang II
Vascular SM
Renal efferent arteriole
Prox renal tubule
Adrenal cortex
Central adrenergic activation
Ganglionic facilitation
Presyn R
Baroreflexes
Role of ACE 2
- Convert Ang II => Ang 1-7
- Act on vascular R => inhibit vasoconstriction + Na+ retention
Ang II R types
- 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
Intracell signaling when binding Ang II R
- 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
RAAS w/ systemic hypertension
Excess vasoconstriction partially mediated by Ang II
RAAS in CHF
- 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
Site of action ACEi
- Bind the same site of ACE on Ang I → block conversion to Ang II
MOA ACEi
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
Major indications for ACEi
o CHF
o Hypertension
o Acute/chronic MI
o Renoprotection
o Diabetic nephropathy
o Cardiovascular protection
