Renin-Angiotensin-Aldosterone-

System RAAS -
Pharmacology

‫פרופ' ג'ריס יעקוב‬

‫ פנימית‬-‫מרכז רקנאטי‬
‫ רמב"ם‬- ‫טכניון‬
 Renin Angiotensin
Aldosterone System = RAAS
One the most important regulatory
systems:
- Extrinsic (renal/hepatic)
- Intrinsic local tissue production
(brain, heart)
- It is pharmacologically well developed:
 Hemodynamics
 Volume determination
 Growth Effects
 Renin-Angiotensin System
Angiotensinogen Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin

Angiotensin I Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin Converting Enzyme-1

Angiotensin II Asp Arg Val Tyr Ile His Pro Phe

Aminopeptidase

Angiotensin Arg Val Tyr Ile His Pro Phe

III
Angiotensinases
various peptidase
Peptide fragments
 Renin-Angiotensin-Aldosterone
System

Sensory Inputs, primarily in Kidney

Renin
Angiotensinogen
ACE-1
ACE-2
Angiotensin I
Angiotensin II
Angiotensin 1-7

Increased Aldosterone Increased

Blood Pressure Na+ Reabsorption Growth of Vascular
(multiple mechanisms) & K+ Excretion and Cardiac Muscle
:Angiotensinogen
 Glycoprotein ~60.000 (15% carbohydrates)
 High Molecular weight (~ 400.000 with other proteins)
 Source: Liver,
Liver and locally in kidney, Brain and fat
tissue
 Plasma levels are correlating with BP values
 Released from the liver spontaneously and is induced
by:
 Inflammation
 Insulin
 Estrogen, OC, Pregnancy (> x5-- involved in HTN)
 Glucocorticoids
 Thyroid hormones
 AII
Renin :((protease enzyme
 Prorenin (406 AA), Renin (340 AA)
 Juxtaglomerular System: granular
cells
 Exocytosis into the afferent arterioles
 Prorenin: renin, 10 : 1
 T1/2 = ~ 15 minutes
 Stimuli………………..
 Juxtaglomerular
Apparatus
 Juxtaglomerular
apparatus is a sensor, for
the regulation of BP and
blood volume

 BP sensed by stretch
receptors in the afferent
arteriole

 Na Delivery to the distal

tubule is sensed by macula
densa

 Both, regulate the secretion

of renin from granular cells
in the juxtaglomerular
apparatus
 Renin Secretion

Sympathetic Macula Renal

NS Densa Baroreceptor
[Na+] Na-K-2Cl BP afferent
arteriole
NE ß1-AR (NO & COX2)
Adenosine, PGs
Stretch
receptors

Juxtaglomerular Cell
cAMP
(-)
Angiotensin
AT1-
RENIN receptor
 Renin Pharmacology:
 Renin blocker  Aliskiren (new)
 SNS activity reducers  Clonidine
 Beta-1 Blockers  Metoprolol,
 PGs production bisoprolol
blockers  NSAIDs, (COX2-
 AT1-antagonists blocker)
 Adenosine (A1)  Losartan
 Drugs affecting [Na]  inhibits secretion
 Drugs affecting BP –  Diuretics (+) renin
indirect effects  Drugs by reducing
BP (+) secretion
 The Renin-Angiotensin
System
Angiotensinogen Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin

Angiotensin I Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin I is rapidly metabolized to AII

Has mild pressor effect
 Renin-Angiotensin System
Angiotensinogen Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin

Angiotensin I Asp Arg Val Tyr Ile His Pro Phe His Leu

Angiotensin Converting Enzyme-1

Angiotensin II Asp Arg Val Tyr Ile His Pro Phe

AII is the principal active peptide of the RAAS system

T1/2 15-30 seconds (destroyed by angiotensinases)
One of the most potent vasoactive peptides
Acts on AT1 (alpha & beta) and AT2 receptors
A Simplified Scheme of the Renin-Angiotensin System

ACE-1
Endothelial cells
membrane
Systemic vasculature
Lung location mainly

MW: 170.000
1277 AA
Zinc is essential for its
activity

Boehm M and Nabel E. N Engl J Med 2002;347:1795-1797

 Dual Role of ACE in blood
pressure regulation
ACE-1

Angiotensin Bradykinin

Vasoconstriction, Vasodilation,
Increased BP Decreased BP
Formation of Angiotensins and Organs Affected by Their Actions

Goodfriend T et al. N Engl J Med 1996;334:1649-1655

 Angiotensin II, Receptors
 Four types of angiotensin receptors (1,2,3
and 4)
 AT1 and AT2 are the most
important
 AT2 is important during fetal stage
 AT2 its expression is low in healthy subjects
 AT2 its role in the adult cardiovascular
system is not well established
A II types 1 (AT 1 ) and 2 (AT 2 ) receptors
Opposing effects
 Angiotensin II actions

Peripheral resistance Renal function

 Potent  Na reabsorption in
vasoconstrictor PT
 Enhances NE release  Releases
in the periphery Aldosterone
 Decreases NE uptake  Alters renal
 Increases central hemodynamics
SNA  Vasoconstriction of
 Increases Adrenaline afferent and efferent
release arteriole
 Vasopressin release
Expression of proto-oncogenes  Thirst (AIII)
Cardiovascular
structure
Increase growth factors
Extracellular protein matrix
Vascular hypertrophy and cardiac remodelling
Role of Angiotensin II and Mechanical Stress in the Generation of Reactive Oxygen Species in
the Vessel Wall in Patients with Hypertension

Sowers J. N Engl J Med 2002;346:1999-2001

Mechanisms of angiotensin II (ANG II)-dependent, oxidant-mediated vascular
damage
 ACE-Inhibitors
Angiotensinogen Asp Arg Val Tyr Ile His Pro Phe His Leu Val Ile His Asn R

Renin

Angiotensin I Asp Arg Val Tyr Ile His Pro Phe His Leu

ACE-
Inhibitors
Block the production of AII
Increase Concentration of AI and renin
Increase concentration of angiotensin 1-7 by endopeptidase (BP,
function ??)
Increase bradykinin and therefore PGs production (effective BP
drop ?)
 Classical ACE-inhibitors
liver Bioavailabil T-1/2 Elimination
ity

Captopril ------ 75% 2h Kidney

enalaprila
Enalapril t 60% 11 h Kidney
ramiprilat
Ramipril 50-60% ? > 18 Liver &
h
kidney
Ramipril has 3-phase elimination
plasma, tissue dissociation
 ACE-I clinical indications
 Hypertension
 Left ventricular dysfunction & CHF
 Diabetic nephropathy
 Nephrotic syndrome
 Renal artery stenosis
 No difference exists between the
various ACE-I
ACE-inhibitors side effects
 Hypotension avoided by titration of dosing
 Hyperkalemia
 Renal failure
 Proteinuria
 Cough: bradykinin ? (1wk-6 mo)
 Angioedema: bradykinin
 Potential teratogenicity
 Liver abnormal function
 Dysgeusia
 Anemia, neutropenia
 Protective against diabetes mellitus !
AT1 Receptor Blockers
(ARBs)
 Highly selective 10000:1 (AT1:AT2)
 Competitive antagonists

 ARBs are more effective in blocking AT1

compared to ACE-I
 Allow activation of AT2

 Circulating AII levels are very high

 Angiotensin 1-7 is less available

 ARBs do not affect bradykinin

metabolism
Which is more effective, ARBs or ACE-I ???
 AT1 Blockers
Peak Bioaviabilit T-1/2 Elimination
y

Candesart 3-4 h < 50% 9 h 70%

an Liver
Exp 3174
Losartan metabolite < 50%
15%:
2-9 h Liver
active
more
potent metabolite CYP450
Valsartan 2-4 h < 50% 9 h Liver

Protein binding is about 90% for

all
 ARBs therapeutic use
 All are approved for hypertension
 Congestive heart Failure (not all)
 Diabetic nephropathy (not all)
 Effective in reducing stroke
 Could be combined with ACE-I
 Combined ACE-I and ARBs in nephrotic
syndrome
 More effective in reducing LVH in HTN
 :ARBs Side Effects
 No angioedema
 No cough
 Much less skin eruptions
 Otherwise similar profile to ACE-I
group.
Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to
Dietary Salt Levels

Aldosterone Antagonists:
spironolactone, eplerenone
Dluhy R and Williams G. N Engl J Med 2004;351:8-10