The Renin-Angiotensin Aldosterone System (RAAS) is the most potent vasoconstrictor system in the body. It was discovered in the 1930s-1940s through experiments involving renal artery clamping and purification of renin. The key components of the conventional circulating RAAS include renin from the kidneys, angiotensinogen from the liver, angiotensin I and II produced via enzymatic cascades, and aldosterone from the adrenal cortex. Angiotensin II is the primary effector peptide and causes vasoconstriction, hypertension, atherosclerosis, and other effects by activating AT1 receptors. Local tissue RAAS also exist and influence organ function.

1. The Renin-Angiotensin Aldosterone System:
Conventional RAS &Established Facts.
Dr Ramachandra Barik

2. INTRODUCTION
In the quest to keep our self updated in the aura of 21st century- newer molecules and newer trials being poring in
everyday, we the upcoming cardiologists are forgetting/confused or do not give importance to the landmarks or
landmark trials in our day to day practice due to lack of time. In the rush of everything should be evidence base
Medicine to do everything at patient 'best and make oneself safest in bar, This is a tiny attempt to afresh our
knowledge of conventional RAS and established facts.
“We repeat the same mistake again and again because we like practice without history.”

3. Bird’s eye View
THE MOST POTENT
VASOCONSTRICTOR SYSTEM
IN THE BODY.

4. Manipulating RAS

5. Recapitulation
• In 1934, pathologist Harry
Goldblatt established the
first animal model of
hypertension. This model
provided researchers with
the tools to delineate the
• RAS -of blood pressure
control and, eventually, to
design enzyme inhibitors
for the treatment of
chronic hypertension.

6. 1836 :Robert Tigerstedt and Per Bergman → kidney–hypertension-LVH.
A thermolabile peptide from kidney extracts into rabbits→HTN=Renin=in kidney.
Kidney
Renin
HTN LVH

7. Harry Goldblatt – 100 Yrs. later a characteristic narrowing of the renal blood vessels in
patients who had died of hypertension-made him think ?????
Renal ischemia ?
Homework-
constricted the major renal
arteries of dogs using a self-
styled adjustable silver clamp.
Partial constriction of both
renal arteries resulted in a Test result
reproducible and persistent Goldblatt’s explanation for his
rise in blood pressure, in the results was similar to that of
absence of overt renal failure. Tigerstedt and Bergman:
Clamping other large ischemia causes the kidneys to
arteries—splenic or femoral— produce an “internal secretion”
had no effect, indicating that that triggers vasoconstriction
hypertension resulted
specifically from kidney
ischemia(Journal of
Experimental Medicine-1934)

8. “Goldblatt’s discovery was spectacular, but nobody believed
it,” recalls cardiologist John Laragh. The skepticism, Laragh says, was largely because of the
technical difficulty of Goldblatt’s procedure, which few could reproduce.
Goldblatt’s confirmed- determining the identity of the “internal secretion”→ Renin.
1939 -Eduardo Braun-Menendez and Irvine Page— purified Renin but found that the higher
the purity lesser the HTN effect .Hence pressure-raising substance not Renin itself rather a
catalyst for angiotensinogen. Purifying renin away from its substrate had abolished its activity .
They named “hypertensin” and “angiotonin,” respectively. They later compromised and
renamed it “angiotensin” and its precursor “Angiotensinogen”.
Leonard Skeggs et al.→ confirmed 2 forms of angiotensin .
It is now known - Renin initiates an enzymatic cascade in which Angiotensinogen is converted
into angiotensin I, which is then processed by angiotensin converting enzyme (ACE) into
angiotensin II. Angiotensin II is the true culprit of hypertension.

9. CONVENTIONAL RAS
(CIRCULATING)
The RAS –endocrine-paracrine-auto crine
(circulatory and local tissue) - true band
master of neurohormonal regulators of
KIDNEY-RENIN
the for circulation in long run.
Renin← JGA cells ← hypo perfusion, ↓&
SNS . Angiotensinogen ← liver cleaved by
Renin→ inactive ANG I→ ACE→ANG
II→ATR for effect by directlyor indirectly.
TARGETS
RAS LIVER-
ANGIOTENSINOGEN
All of the necessary components of the
RAS also exist in several organs and
tissues, including the heart, kidneys, and
vasculature.
LUNGS-ACEI

10. Ang II Aldo Pleotropy
Affects → heart & systemic RESULTS
vasculature Vasoconstriction, Atherosclerosis,HTN,cardiac
Athesclerosis, vascular Hypertrophy.etc
remodeling, hypertrophy,
interstitial fibrosis, apoptosis,
inflammation, thrombosis,
Angiotensin II–stimulated
secretion of aldosterone by the
adrenal cortex and arginine
vasopressin , sympathetic
activation and aldosterone.

11. Renin –
Hormonal peptide-340 AA,an enzyme .
T½ -15 min ,prepared and stored in
granular JG cells in kidney and also other
tisuue–the main source of plasma Renin
(active) and 90% in prorenin (inactive
but immune reactive ).it is synthesized In
both constitutive and rate limiting
pathway. It catalyzes the rate limiting
step of RAS – attract active future target.
Stretch receptors(pressure sensor) in the
afferent arteriole, local SNS , Na content
of the tubular fluid reaching the macula
Desna cell - release around JGA→Renin .

13. ↑ RELEASE

14. Renin production is ↓ indomethacin,b-Blocker,Ang II receptor and pepstatin.

15. Rate-limiting step : α2
globulin, angiotensinogen(453
AAs-↑ by glucocorticoids,
thyroid hormones, estrogens,
several cytokines, and
angiotensin II) by Renin →
inert decapeptide Ang- I(1/100
th potency of Ang II)→ Ang
II(T½-1 min).Source of
Angiotensinogen- liver, kidney,
brain, heart, vascular, adrenal
gland, ovary, placenta, and
adipose tissue.
ACE-ectoenzyme two forms:
a somatic - throughout the
body and a germinal cell. One
gene chromosome 17.
(DD/II/DI) . Angi I→Ang
II.Localized in plasma
membrane of endothelial cells
and other cells in unbound
form in plasma. Angi II - III and
IV.Angi II -T½ IS 1-2 min .

16. Conventional/tissue RAS

18. RAS WORKS-
Renin –rate limiting enzyme.
Angiotensinogen-renin substrate from liver.
Angiotensinogen I–no action.
Angiotensin II=hypertensin = angiotonin—
most potent vasoconstrictors X8 NA.its
pressure activity ↓in Na+, cirrhosis .
Angiotensin II ↑adrenal cortex Aldosterone
secretion, nor epinephrine by a direct action
on postganglionic sympathetic neurons,
contraction of mesangial cells (↓ GFR),direct
renal tubules to increase Na+ reabsorption.
Angiotensin II → brain to decrease the
sensitivity of the baroreflex→potentiates the
pressure effect of Angiotensin II/↑ H20
intake/ vasopressin and ACTH. It does not
penetrate the blood–brain barrier, but it
triggers these responses by acting on the
circumventricular organs, One of these
structures, the area postrema- pressure ↑
subfornical organ (SFO) and the organum
vasculosum of the lamina terminalis (OVLT),
cause-dispogenic effect.

19. Angiotensin II Receptors-
AT1- (chromosome 3/Gq- phospholipase C-
IP3/DAG - intracellular ↑ cytosolic Ca2+ -
vasopressor and contraction of heart and
tyrosine kinase/MAP kinase /PKC-
protooncogene activation for growth and
hyperplasia.)- effects of Ang II.
AT2—( X chromosome/ G protein
/phosphatases -antagonize growth effects and
open K+ channel/production of NO and
↑intracellular cyclic 3,5-guanosine
monophosphate (cGMP). . AT2 receptors -
plentiful in fetal /neonatal life / also in brain
and other organs in adults.
The AT1 receptors in the arterioles and the AT1
receptors in the adrenal cortex are regulated in
opposite ways: an excess of angiotensin II down-
regulates the vascular receptors, but it up-
regulates the adrenocortical receptors, making
the gland more sensitive to the Aldosterone-
stimulating effect of the peptide.

22. Angiotensin III –has 40% of
the pressure activity of
Angiotensin II, but 100% of the
Aldosterone-stimulating
activity. It has been suggested
that Angiotensin III is the
natural Aldosterone-
stimulating peptide, whereas
Angiotensin II is the blood-
pressure-regulating peptide.
However, this appears not to
be the case, and instead
Angiotensin III is simply a
breakdown product with some
biologic activity.
Angiotensin IV- unique effects
in the brain.

26. AT-2 receptor
A single gene on the X chromosome.
highly expressed in fetal mesenchyme tissues
clearly detectable in the adult kidney, heart, and blood vessels.
mediate vasodilation by stimulating the production of BK, NO, and cGMP.
activates phospholipase A2 and prostaglandin generation.
 In the heart, the AT2 receptor inhibits growth and remodeling, induces vasodilation, and is up-
regulated in pathological states
Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor
blockade via a BK/NO/cGMP pathway.
This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor
agonists in combination with AT1 receptor blockers.
Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor
blockade via a BK/NO/cGMP pathway.
This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor
agonists in combination with AT1 receptor blockers.

27. AT-III AND AT –IV RECEPTOR
The type 4 (AT4) receptors- mediate the release of plasminogen activator inhibitor 1 by Ang II
and by the N-terminal truncated peptides (Ang III and Ang IV).
The AT4 receptor appears to be involved in memory acquisition and recall.
 but the function of the type 3 (AT3) receptors is unknown.

31. 2000 AD -ACE 2 a zinc metalloprotease was discovered and gene mapped X-chromosome
ACE 2 may be a candidate gene in hypertension.

32. Predominantly in endothiuelm of coronary and renal vasculature
 ACE 2 probably counterbalances the enzymatic actions of ACE
Unlike ACE, this enzyme does not convert Ang I to Ang II and its activity is not affected by ACE
inhibitors
MAS -G protein-coupled receptor originally described as a proto-oncogene
expressed in several organs including heart, kidney, blood vessels, and brain
intracellular signaling mechanisms are largely unknown may be coupled to a Gq/11 protein
that activates phospholipase C (PLC).
BRADYKININ-In addition to BK potentiation at B2 receptor, promotes release of prostaglandins
release of NO { PI3K/Akt pathway} vasodilation, inhibition of vascular cell growth,
attenuation of ANG II-induced vasoconstriction In addition to BK potentiation at B2 receptor,
promotes release of prostaglandins release of NO { PI3K/Akt pathway} vasodilation,
inhibition of vascular cell growth, attenuation of ANG II-induced vasoconstriction

33. Prorenin receptor
Transmembrane protein consisting of 350 amino acids ;cloned from mesangial cells
 Prorenin/renin - not only aspartyl proteases but also hormones with specific cellular actions in
their own right.
Relevant to the pathophysiology of hypertension, preeclampsia, and diabetes mellitus.
pathogenic mechanism dually activates the tissue Renin-Angiotensin system (RAS) and RAS-
independent intracellular signaling via the receptor.
pathogenic mechanism dually activates the tissue Renin-Angiotensin system (RAS) and RAS-
independent intracellular signaling via the receptor.
 Activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)
pathway and increases several profibrotic mediators- (TGF-β), and (PAI-1), and the extracellular
matrix components, fibronectin and collagen
receptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface
by receptor-bound prorenin and renin
 Activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)
pathway and increases several profibrotic mediators- (TGF-β), and (PAI-1), and the extracellular
matrix components, fibronectin and collagen
receptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface
by receptor-bound prorenin and renin

34. Tissue RAS.
In addition to circulating Angiotensin II, many different tissues contain independent
renin–angiotensin systems that generate Angiotensin II, local use account for 90%
of total ANG II. found in the walls of blood vessels and in the uterus, the placenta,
and the fetal membranes. Amniotic fluid has a high concentration of prorenin. n the
eyes, exocrine portion of the pancreas, heart, fat, adrenal cortex, testis, ovary,
anterior and intermediate lobes of the pituitary, pineal, and brain. Tissue Renin
contributes very little to the circulating Renin pool, because plasma Renin activity
falls to undetectable levels after the kidneys are removed. The functions of these
tissue renin–angiotensin systems are unsettled, though evidence is accumulating
that Angiotensin II is a significant growth factor in the heart and blood vessels. ACE
inhibitors or AT1 receptor blockers are now the treatment of choice for congestive
heart failure, and part of their value may be due to inhibition of the growth effects
of Angiotensin II.

35. Manipulating RAS-Towards establishing facts
1.Sympathetic blocker-ᵦ blocker, adrenergic neuron blocker, central sympatholytic ↓renin.
and interventional therapy-SNS radio frequency ablation for RAS.
2.Renin inhibitory peptides and antibody ↓ Renin
3.ACEI
4.Ang AT1 receptor blocker
5.Ang II activator
6.Aldosterone antagonist
7.AT2 receptor agonist
8.Prorenin receptor blocker?
7.Vasopeptidase inhibitor.?
7.Vaccines?
8.Genetic ?

42. Renin inhibitor

43. Renin blocker-alskerin

49. RALES,EPHESUS

50. AT1-Receptor Blocker (ARB)
Clinical Outcome Studies
HBP VASCULAR MI HF
LIFE (ONTARGET) OPTIMAAL ELITE II
SCOPE (TRANSCEND) VALIANT Val-Heft
VALUE JIKEI
CHARM
(I-PRESERVE)
PRE-DIABETES DIABETES DIABETES RENAL
(NAVIGATOR) OPTHAL
(DIRECT) RENAAL
ATRIAL FIB IDNT
(ACTIVE)

51. AECI/ARB COMBINED
cardiovascular outcomes [ CHARM-Added, Val-HeFT, VALIANT vs
RESOLVD Pilot Study Investigators ] may relate to different
patient populations, previous or concurrent successful treatment
with other drugs, or study design
PRA is related to adverse clinical outcomes further raises the
possibility that DRIs may be useful.
In heart failure –FDA approved

52. Established facts
1.RAS INHIBITION IS BENIFICIAL
2.CHF-VERY USUFUL IN MILD/MOD/SEV HF
3.HTN-BEST RESULTS WITH LONG TERM USE AND WITH HIGH RISK PATIENTS
4.EARLY MI START WITHIN 24 HOURS.
5.ASYMPTOMATIC LV DYSFN-SAVE,SOLVED
6.JUVENILE DM
7.NON DM NEPHROPATHY
8.PROPHYLAXIS-HIGH RISK-HOPE/EUROPA,ONTARGET
9.ARB/HF-VALIANT
10.COMBINATION THERAPY-VAL-HeFT,CHARM ,ON TARGET
11.LESS NEW DM-COMPAIRED b –blocker/diuretic.
12.B/L RAS,PREGNANCY,HYPERKALEMIA,HIGH CREATINE
13.ALDACTONE/SPIRONOLACTONE IN HF/MI
14.ALISKERIN-ALTITUDE/ASPIRE
14.QUADRUPLE THERAPY.

53. THANK U