Transcript PHYSIOLOGY OF RAAS_ DR SANDEEP R.ppsx

DR.SANDEEP R
SR , DEPT. OF CARDIOLOGY
CMC CALICUT

1) HISTORY

2) ANGIOTENSINOGEN

3) RENIN

4) ACE

5)ANGIOTENSINS

6)ANGIOTENSIN RECEPTORS

7)LOCAL RAAS

8)CARDIAC RAAS

9)ALDOSTERONE

9)PATHOPHYSIOLOGY OF RAAS
HISTORY

Robert Tigerstedt and Per Bergman from Sweden in their
seminal 1898 report, Niere und Kreislauf, described the
prolonged vasopressor effects of crude rabbit kidney
extracts.

Tigerstedt named the unidentified active substance “renin”
on the basis of its organ of origin.
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

Goldblatt and colleagues, published in 1934, that showed that renal ischemia induced
by clamping of the renal artery could induce hypertension.

Ischemic kidney also released a heat-stable, short-lived pressor substance, in
addition to renin.

This finding eventually led to the recognition that renin’s pressor activity was indirect
and resulted from its proteolytic action on a plasma substrate (eventually termed
“angiotensinogen”) to liberate a direct-acting pressor peptide.

This peptide was initially termed “angiotonin” or “hypertensin” by Page &
colleagues(US)

Ultimately named “angiotensin” by Braun-Menendez & colleagues(ARGENTINA)
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

In the early 1950s, during attempts at purification, Skeggs &
colleagues discovered that this peptide existed in 2 forms,
eventually termed Ang I and II.
In later work, they demonstrated that Ang I was cleaved by a
contaminating plasma enzyme,termed “angiotensin-converting
enzyme,” to generate the active pressor peptide Ang II.

Laragh, Genest, Davis, Ganong, and their colleagues, culminated
in the discovery that Ang II also stimulated the release of the
adrenal cortical hormone aldosterone
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
ANGIOTENSINOGEN

The primary source of systemic circulating angiotensinogen is the liver
particularly the pericentral zone of the hepatic lobules.

It is coded by a single gene, composed of five exons and four introns, that spans
approximately13 kb of genomic sequence on chromosome 1 (1q42-q43).

Also detected in many other tissues, including kidney, brain, heart, vascular,
adrenal gland, ovary, placenta, and adipose tissue

Rise in response to glucocorticoids, estrogens and other sex steroids, thyroid
hormone, inflammatory cytokines (e.g., interleukin-1 and tumor necrosis factor),
and Ang II.
Ron D, Brasier AR, Habener JF. Angiotensinogen gene-inducible enhancer-binding protein 1, a member of a new family of large nuclear
proteins that recognize nuclear factor kappa B-binding sites through a zinc finger motif. Mol Cell Biol. 1991;11:2887-2895.
RENIN

Glycoprotein (Mw 37,326)

Renin gene located in CHR.1

Synthesized from preprorenin

Mature active renin is an aspartyl
protease secreted by
juxtaglomerular cells
Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;384-385
JUXTAGLOMERULAR APPARATUS

(1)
The Juxtaglomerular
Apparatus consists of:
The juxtaglomerular cells
(2) The macula densa
(3) The lacis cells or agranular
cells
RENIN -SYNTHESIS
PREPRORENIN( 406 aminoacid)
PRORENIN (383 aminoacid)
RENIN (340 aminoacid)
Renin is also synthesized In brain, adrenal gland, ovary, visceral adipose tissue,
heart and vasculature
Half life of renin is 80 mt
Only action of renin is conversion of angiotensinogen to angiotensin I
REGULATION OF RENIN

Active renin secretion is regulated principally by 4 interdependent
factors:

(1) A renal baroreceptor mechanism in the afferent arteriole that
senses changes in renal perfusion pressure,

(2) Changes in delivery of NaCl to the macula densa cells of the
distal tubule

(3) Sympathetic nerve stimulation via beta-1 adrenergic receptors

(4) Negative feedback by a direct action of Ang II on the JG cells.
HAYO CASTROP, KLAUS HO ¨ CHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR TODOROV,
AND CHARLOTTE WAGNER; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;
REGULATION OF RENIN SECRETION


1.INTRARENAL MECHANISM
Renal baroreceptor mechanism

Renin secretion increases as the blood pressure falls below 90mmhg

The precise mechanism , how the pressure signal is transduced into renin release is still unknown,
although postulated mediators include stretch-activated calcium channels, endothelins, and
prostaglandins


JG cells are strongly electrically coupled to the neighboring cells of the afferent arteriole .
Interestingly, their resting membrane potential changes in situ from -60 to -80 mV in nonpressurized
arterioles to approximately -40 mV in pressurized arterioles

Since the depolarization of JG cells is accompanied by the suppression of renin release, the
depolarization in response to an increase in perfusion pressure might directly or indirectly contribute to
the known pressure-dependent inhibition of renin secretion
HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;
2.NEURAL CONTROL

The JGA is endowed with a rich network of noradrenergic nerve
endings and their β1 receptors

Stimulation of the renal sympathetic nerve activity leads to renin
secretion that is independent of changes in renal blood flow, glomerular
filtration rate (GFR), or Na+ resorption

Moreover, this effect can be blocked surgically by denervation and
pharmacologically by the administration of β blockers

3.TUBULAR CONTROL

Chronic diminution in luminal NaCl delivery to the macula densa is a
potent stimulus for renin secretion

This mechanism is thought to account for the chronically high plasma
renin activity (PRA) in subjects who adhere to a low-salt diet

The initial step of the MD-dependent control of renin secretion is the
detection of the NaCl concentration in the tubular lumen by the MD cells.
HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;
DISTAL TUBULAR SODIUM ↑
INCREASED UPTAKE INTO MACULA DENSA
THROUGH NA/K+/2CL CHANNEL
MACULA DENSA Na+ & FLUID CONTENT↑
SWELLING OF MACULA DENSA & STRETCH
STRETCH CAUSES ADENOSINE RELEASE
A2 CAUSES ↓
RENIN SECRN
NO SYNTHETASE ↓
DECREASES RENIN

DISTAL TUBULAR SODIUM ↓
Na+ UPTAKE IN MACULA DENSA ↓
ACTIVN OF NO
SYNTHETASE
PG SYNTHESIS
STIMULATE RENIN
RELEASE

The detection done by Na-K-
2Cl cotransporter in the apical
membrane of tubular cells

Three mediators prostanoids, NO, and
adenosine/ATP
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010
REGULATION OF RENIN
FACTORS THAT DECREASE
RENIN RELEASE

1)
2)
3)
4)
5)
6)

ANG II
VASOPRESSIN
ANP
IL6
TNF - ALPHA
ADENOSINE




FACTORS THAT
INCREASE RENIN
RELEASE
1)Catecholamines
2)Bradykinin
3)Dopamine
4)NO
5)Prostaglandins
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010
MOLECULAR MECHANISM OF RENIN RELEASE

C-amp mediated sympathetic, prostaglandin E2
& I2,dopamine

Calcium paradox - increase in
intracellular Ca2+ decrease
renin releaseendothelin,vasopressin,Ang II

C-GMP
Low consc. stimulates &
High consc. Inhibits - NO
Castrop et al ; Physiology of Kidney Renin Physiol Rev 90: 607–673, 2010
PRORENIN

Traditionally, prorenin was considered the inactive precursor of renin

The Current studies implicate prorenin and renin as direct cardiac and
renal toxins
Prorenin is inactive because a 43–amino acid hinge is closed and
prevents it from binding to angiotensInogen


Prorenin & renin levels increased by ACE inhibitor , ARB , DRI
Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;384-385
PRORENIN RECEPTOR

The kidneys convert inactive
prorenin to active renin by
enzymatic cleavage of this
inhibitory hinge region

When circulating prorenin
binds to a newly discovered
(pro)renin receptor in the
heart and kidneys, the hinge
is opened (but not cleaved),
and this nonenzymatic
process fully activates
prorenin
Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP
October 2007
Vol. 13, No. 8, S-b
RENIN/PRORENIN RECEPTOR

The existence of high-affinity cell surface receptors that bind both renin
and prorenin in several tissues, including heart, brain placenta, and
kidney but its significance still unknown

The binding of renin to its receptor resulted in a fivefold increase in the
catalytic activity compared with renin in solution

The binding of pro-renin to the receptor increased its enzymatic activity
from virtually zero to values comparable to those of active renin in
solution

Activation of the (pro)renin receptor increases TGF-β production, leading
to collagen deposition and fibrosis
Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP
October 2007
Vol. 13, No. 8, S-b
ACE

ACE is responsible for the cleavage of
Ang I to form the octapeptide Ang II

ACE cleaves bradykinin into inactive
fragments

Human ACE in encoded by a single
gene located on chromosome 17

The majority (∼90%) of ACE activity in
the body is found in tissues; the
remaining 10% of ACE activity is found
in a soluble (non–membrane bound)
form in the interstitium of the heart and
vessel wall

It is seen pulmonary vascular
endothelium, endothelium of
vasculature ,cell membrane of heart ,
kidneys & brain
ACE 2

ACE2 represents a zinc metalloprotease with carboxypeptidase activity
that shares 42% identity with the catalytic site of somatic ACE and can be
shed from cells

ACE2 can convert ANGII to ANG 1-7 & ANG I to ANG 1-9

Preferable physiological substrate for ACE2 seems to be ANG II

The expression of ACE2 is (in comparison with ACE) relatively restricted to
cardiac blood vessels and tubular epithelia of the kidneys

ACE 2 cannot hydrolyze bradykinin and is not inhibited by ACE inhibitors

Actual function and significance is still unknown

ACE2 is the functional receptor for coronavirus associated with the acute
respiratory syndrome, i.e., SARS
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition J Manag Care Pharm. 2007;13(8)(suppl
S-b):S9-S20
ANGIOTENSIN SYNTHESIS
ANGIOTENSIN RECEPTORS

ANGIOTENSIN RECEPTORS

1)AT1

2)AT2

3)AT3

4)AT4

5)Mas receptor
AT1 RECEPTOR

AT1 - G protein coupled receptor

Chromosome 3

AT1A receptors are found predominantly in kidney, lung, liver and
vascular smooth muscle

AT1B receptors are expressed mainly in the adrenal and anterior
pituitary glands.
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

AT1 receptors are primarily found in the

1)Brain-hypothalamus,NTS and ventrolateral medulla in the
hindbrain,ant.pituitary

2)Adrenals- the zona glomerulosa of the adrenal cortex and
chromaffin cells of the adrenal medulla

3) Heart - in the conducting system , nerves of myocardium

4)Vasculature-the aorta, pulmonary and mesenteric arteries, are
present in high levels on smooth muscle cells and low levels in the
adventitia

5) Kidney – glomerular mesangial cells and renal interstitial cells
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
AT1 RECEPTOR

The predominant angiotensin
receptor in the vasculature is
the AT1 receptor

Although both the AT1 and
AT2 receptor subtypes are
present in human myocardium

Ratio of AT1 to AT2 receptors
decreases in heart failure
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
ACTIONS OF AT1 RECEPTOR

1) Blood vessels –
vasoconstriction leading to
an increase in peripheral
vascular tone and systemic
blood pressure
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

2)Heart

Positive ionotropic and
chronotropic effects of Ang II
on cardiomyocyte

1)INCREASED
SYMPATHETIC ACTIVITY

2)INCREASED CA2+
INFLUX

Ang II is also known to
mediate cell growth and
proliferation in cardiac
myocytes and fibroblasts, as
well as in vascular smooth
muscle cells via TGF,PDGF
etc
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

3) Adrenal -Ang II stimulates the release of catecholamines from the
adrenal medulla and aldosterone from the adrenal cortex

Trophic factor for zona glomerusa

4) Brain- thirst , salt appetite, central control of blood pressure,
stimulation of pituitary hormone release and has effects on learning
and memory
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

5)RENAL

It increases salt reabsorbtion – direct & indirect

Direct effect
Renal arterioles constriction
Proximal Tubular
Epithelial cells
Sodium
reabsorbtion
Peritubular capillary pressure
Fluid reabsorption
From tubules
INDIRECT ACTION OF ANG II IN KIDNEY

ANGIOTENSIN II
ADRENAL
CORTEX STIMLN.
SYMPATHETIC ACTIVATION
ALDOSTERONE
SECRETION
MESANGIAL CONTRN
GFR
SALT & WATER
RETENTION
AT2 RECEPTOR

The AT2 receptor is also a seven transmembrane domain receptor, encoded
by a 363-amino-acid protein( MW 41 kDa)

Shares only 34% sequence identity with the AT 1 receptor

The AT2 receptor -highly expressed in foetus but rapidly declines at birth

AT2 receptors are present in brain, heart, adrenal medulla, kidney and
reproductive tissues
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
AT2 RECEPOR & ITS ACTIONS

Brain – cerebellum

Heart - fibroblasts in interstitial
regions

Adrenal- adrenal medulla

Kidney- the AT2 receptor is
localized to glomeruli, tubules
and renal blood vessel

ACTIONS

Vasodilation

Antiproliferative

Apoptosis

Thirst
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
AT3 & AT4
Type 3 (AT3) receptors – Function unknown
The type 4 (AT4) receptors - mainly mapped in brain & kidney

Thought to mediate the release of plasminogen activator inhibitor 1 by
Ang II and by the N-terminal truncated peptides (Ang III and Ang IV)

Suggested a role in mediating cerebral and renal blood flow, memory
retention and neuronal development
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
Mas RECEPTOR
Mas receptor - Acted upon
by ANG1-7
Causes
1)
Vasodilatation
2)
Natriuresis
3)
Antiproliferation
4)
Cardiac protection
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010
LOCAL RAS

Angiotensin II is found to be synthesized in the various tissues through
ACE & non ACE pathways

Independent Ang II - heart, peripheral blood vessels, kidney, brain,
adrenal glands, pituitary, adipose tissue, testes, ovaries, and skin.

COMPONENTS :
1) Renin and Prorenin receptor
2) Serine proteases, including several kallikrein-like enzymes (tonins),
cathepsin G, and chymase are thought to contribute to Ang II
3) Non-ACE pathways- chymase is the dominant Ang II-generating
pathway in the human heart, coronary arteries, and atherosclerotic
aorta in vitro
4)ACE 2 ,Mas receptor,AT2 , AT4




The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition Vol. 13, No. 8, S-b
October 2007
JMCP
LOCAL RAS
CARDIAC RAAS
1)RENIN
2)RENIN RECEPTOR
3)ANGIOTENSINOGEN
4)CHYMASE
5)ACE 2
6)AT1& AT2
1
RECEPTOR
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006


CARDIAC RAS
Predominant physiological role of the cardiac RAS appears to be the
maintenance of an appropriate cellular milieu balancing stimuli inducing
and inhibiting cell growth and proliferation as well as mediating adaptive
responses to myocardial stress, for example, after myocyte stretch
EFFECTS OF CARDIAC RAAS

1)Ionotropic Effect

Positive ionotropic and chronotropic effects of Ang II on
cardiomyocyte
1)INCREASED SYMPATHETIC ACTIVITY
2)INCREASED CA2+ INFLUX

2)Hypertrophy

Ang II is also known to mediate cell growth and proliferation in
cardiac myocytes and fibroblasts, as well as in vascular
smooth muscle cells via TGF,PDGF
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

3)Mechanical stretch- stretch can cause release of ANG II
causing hypertrophy and remodelling

4)Cardiac remodelling – stretch causing fibroblast activation
through AT1 receptor.

Increased activity of the system has also been linked to
changes in the electrical physiology that lead to arrhythmias
both in the ventricle and atria

5) Apoptosis – remodelling during M.I , DCMPY etc
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

VASCULATURE RAS

1) Vasoconstriction

2) Oxygen free radicals causing endothelial dysfunction

The production of ROS by NAD(P)H oxidase in reponse to ANG II
stimulation in endothelial and vascular smooth muscle cells
activates signal pathways such as MAP kinases, tyrosine kinases
may lead to inflammation , artherosclerosis, hypertrophy

3)Angiogenesis
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

GENDER DIFFERENCES IN CARDIAC RAS

1)AT1 receptor downregulated by estrogen

2)Increased pdn. Of ANG 1-7 –vasodilator peptide

3)Ventricular ACE activity is more in males

4)Estrogen decreases renin production

5)Angiotensinogen production is stimulated by testosterone
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006
ALDOSTERONE







Mineralocorticoid
It is synthesized in the zona glomerulosa
of adrenal cortex
It is stimulated by
1)ACTH
2)ANG II
3)HYPERKALEMIA
4) HYPONATREMIA

Cholesterol
ACTH/AII
Pregnenolone
Progesterone
Deoxycorticosterone
ALDOSTERONE SYNTHASE
Corticosterone
ALDOSTERONE SYNTHASE/AII
18-Hydroxycorticosterone
ALDOSTERONE SYNTHASE
Aldosterone
MINERALOCORTICOID RECEPTOR

Mineralocorticoid receptor can
bind cortisol, aldosterone &
deoxycortisone

The affinity of cortisol to MR
receptor is ten times its affinity to
GR receptor

This is prevented by the presence
of 11 beta dehydrogenase 2
which converts cortisol to
cortisone( inactive )

This is the basis of syndrome of
apparent mineralocorticoid
excess (AME)
PERRIN C. WHITE:Aldosterone: Direct Effects on
and Productionby the HeartThe Journal of Clinical
Endocrinology & Metabolism 88(6):2376–2383
ALDOSTERONE ACTION
Acts on P cells in
Collecting duct
Causes increased
activity of Enac
Causes Na/K
exchangers
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
REGULATION OF ALDOSTERONE
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
FEEDBACK REGULATION OF ALDOSTERONE
HARMFUL EFFECT OF ALDOSTERONE
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
EFFECTS OF ALDOSTERONE ON HEART

1)Cardiac fibrosis - by acting through mineralocorticoid receptor in
cardiac fibroblast causing activation of MAP kinase

2)Perivascular inflammation- endothelial dysfunction permitting
adhesion of inflammatory cells to the vascular wall and egress into the
perivascular space
Indeed, aldosterone causes endothelial dysfunction in humans in vivo
possibly by decreasing NO through superoxide generation
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383


3)Cardiac hypertrophy
Increased intracellular calcium might ultimately cause cardiac
hypertrophy by increasing the expression of calcineurin, a
calcium/calmodulin-dependent protein phosphatase

Increase ACE activity causing ANGII causing hypertrophy
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

4) Electrophysiologic
abnormalities in heart

Aldosterone causes increase in
intracellular calcium/increase in
sodium flux which may cause
arrythmia

All enzymes required for synthesis
of deoxycorticosterone and (in the
atria) corticosterone are
expressed in the normal human
heart
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
‘ONE KIDNEY’ GOLDBLATT HYPERTENSION

Initial rise in hypertension is due
to renin secretion leading to
angiotensin II

Secretion of renin peaks in one
day but gradually decreases
over 5-7 days as the renal
perfusion improves

Second rise is due to increase
in aldosterone
“TWO KIDNEY” GOLDBLATT HYPERTENSION

If there are two kidneys and
one is clamped

Then the ischaemic kidney
releases the renin

This renin causes fluid and
salt retention in both the
normal and abnormal kidney

This leads to hypertension
RAS IN HEART FAILURE

In contrast to the sympathetic nervous system, the
components of the RAS are activated comparatively later in
HF

The presumptive mechanisms for RAS activation in HF
include
1) Renal hypoperfusion
2)Decreased filtered sodium reaching the macula densa in
the distal tubule
3)Increased sympathetic stimulation of the kidney, leading to
increased renin release from the juxtaglomerular apparatus



Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
BIBLIOGRAPHY









1)Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and
Pharmacologic Inhibition J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
2) PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of
Clinical Endocrinology & Metabolism 88(6):2376–2383
3) MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local ReninAngiotensin Systems Physiol Rev 86: 747–803, 2006
4) Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science
(2001) 100, ;481–492
5) Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October 2007 Vol. 13,
No. 8, S-b
6) Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF
NEPHROLOGY;2010;12;384-385
7) HAYO CASTROP, KLAUS HO ¨ CHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR
TODOROV,AND CHARLOTTE WAGNER; Physiology of Kidney Renin: Physiol Rev 90: 607–673,
2010;
8) Ron D, Brasier AR, Habener JF. Angiotensinogen gene-inducible enhancer-binding protein 1, a
member of a new family of large nuclear proteins that recognize nuclear factor kappa B-binding sites
through a zinc finger motif. Mol Cell Biol. 1991;11:2887-2895.
9)GUYTON &HALL MEDICAL PHYSIOLOGY 12TH EDITION