Today we are going to talk about the Renin
Angiotensin Aldosterone Axis or the System,right.
It is one of the very important physiological
system which is doing lot of function, but
most important function is Blood Pressure
Regulation.
That how this system regulates your blood pressure.So
let's start first to understand its physiology,right.
And to understand its physiology, let's
take an example that due to some reason if my
blood pressure is going down, for example,
I develop some haemorrhage or bleeding,
I am losing the blood out of my body.
Then how the system is activated?Because the
duty of the system is, duty of renin angiotensin
aldosterone system is to maintain my blood
volume and to maintain my blood pressure.
Volume and pressure in the vascular system should
be regulated by this system, it plays one
of the very important role.Let's disturb the
volume and pressure and see what happens to
this system.Example we take that there is
a patient, and he got in roadside accident,
and he is losing blood, right.
Of course.Now we'll discuss that how the system
is activated.Let suppose that
this is the circulatory system of that patient, right.The
organs which are going to play a role
in this whole game is; number one, Central Nervous System, which is responsible for sympathetic
outflow, we will talk about the kidney, Is that right? Rather drawing the full kidney
we'll draw a nephron here,right.So i'll draw
a small kidney here,right.Then there is a
role played by the liver.We'll talk about
that what is that role, and then very important
role is played by pulmonary circulatory system.
And of course,we'll not forget the role which
is played by adrenal cortex.So let's start
one by one.What really happens that when your
patient is bleeding, let's suppose patient
is losing the blood here, naturally blood
pressure is going down, and blood volume is
going down.Is that right?
Many things will happen in the body. One
of the thing which will happen that, if patient
is bleeding and blood pressure goes down, the
blood flow to kidney will increase or decrease?
Decrease.
So first thing we'll say, there's reduced renal
perfusion.
Now, whenever there is reduced renal perfusion, right,
then veins from the kidney, the veins from
the kidney start bringing an enzyme in the
blood.
This enzyme is released in blood from the kidney.
This enzyme is called Renin.
What I've said that whenever blood pressure
goes down, kidneys start producing more renin
and more renin come into blood.
But first of all, we must study the kidney
thoroughly that by reducing the blood pressure,how
kidney start producing renin,right.For this
purpose, I will bring one nephron out and
show in the nephron the apparatus which is
suppose to release renin.
One kidney has how many nephrons?
You know kidneys have very specialized tube.You
are milloinaire as far as nephrons are concerned.In
one kidney there are about 1.2 million nephrons.But
I will just bring out of this kidney one nephron
out, right.Let's suppose this is the nephron
here, and this nephron I am going to draw
outside to explain that how really this system
work.This is one epithelial tube of nephron
from the kidney, right.And we'll see how normally
this nephron works in relationship to blood
supply.Let's suppose this is afferent arteriole
which is bringing the blood to the nephron, these
are glomerular capillaries, and here is efferent
arteriole.What is this?This is afferent arteriole.Here
it is efferent arteriole, right, and here is
your nephron. Now what really happens, that
we say that blood is, patient is bleeding,
naturally blood coming to kidney is less,
so of course blood flow to this nephron is
also less.So afferent arteriole has poor blood
flow. Now there is very interesting thing, nature
has put blood pressure measuring devices
with every nephron. What a master system in
the nature that nature has put blood pressure
measuring device with every nephron, so that
every nephron knows how much blood is coming
to it, is it enough or not.
So Mr. Hadayat you will tell me what is
the blood pressure
measuring device with every nephron?
Anyone has idea about? You have any idea? Every
nephron has blood pressure measuring device.
If you have 2.5 million nephrons right now in
is your two kidneys, there are 2.5 million
blood pressure measuring devices with every
nephron.Let me tell you one thing, you see
what is this?
This was afferent arteriole.The smooth muscles,
these are the normal smooth muscles on afferent
arteriole. As afferent arteriole approaches
the, what is this?
Glomerulus, right, its smooth muscles become
altered, they are no more normal smooth muscles.
These are very specialized smooth muscles, right. And
this group of very specialized smooth muscles
which are present in the wall of afferent nephron,
sorry afferent arteriole, this is blood pressure
measuring device.These are the Baroreceptors,
it means nature consider blood flow to nephron
extremely important.That is why nature measures
the blood flow to every nephron, right.
And this whole group, it has been given a
special name, the name is called Polkissen, Polkissen.
So what is Polkissen?
Polkissen are made of a special apparatus, which
is made of what?
Modified afferent arteriolar smooth muscles
which are able to
measure the blood flow to nephron.
And whenever blood flow to nephron become
less, whenever the blood flow to nephron become
less, they start releasing renin into blood.
So it means they have double actions; one
action is to measure the blood flow, and second
action is to release the renin.
It means they're acting like an Endocrine
gland, because one group of cell releasing
the hormone into blood, and acting into some
distant area.
So every nephron has small endocrine system
with it.
Am I clear?
This is the blood pressure measuring device.
Whenever your blood flow is coming less, and
there's less pressure on this apparatus.
As soon as this apparatus sense that blood
flow is less , or blood pressure is less,
it will start releasing which substance?
Renin, okay, write it like this, it is the
renin.
So this is one way how renin is released by
the special apparatus from the nephron.
Now, another mechanism is also there.
First understand normal.
Normally what happens, that when blood is moving
through the glomerular capillaries,
there is some filtration done, there is glomerular
filtrate, am I clear?
Now, this glomerular filtrate normally has
lot of sodium and many other substances.
Of course, what are these?
These are the cells in the wall of nephron,
right.
Now listen, nephron has lot of cells in its
wall.
Now you see, normally when there is normal
blood flow, then there is normal filtration,
and filtration normally is about 120 ml per
minute in the all nephron.
This filtered material start going down but
because it is lot of sodium, nephron cells
take the sodium back to the body. Is that right?
About 70% of the sodium or 60-70% of the sodium 
which is filtered as it is moving through
proximal convoluted tubule, it is reabsorbed
back to the body.
We don't want to lose the sodium.
Then sodium keeps on moving forward, and about
25% of sodium is reabsorbed here.
If 65% sodium, if 100 unit of sodium go down,
65 is reabsorbed here, and 25 is reabsorbed
here, how much is left? I think your
maths is not okay. 65 plus 15?
Student: 25.
65 plus 25, how much it become?
90.
It means normally out of the filtered sodium,
about 10% sodium comes here on this bend.
This is the end, this is the beginning of
distal convoluted tubule and end of the thick
part of ascending limb of Loop of Henle. Here, 
nature has put a very beautiful system.
There are some cells here which are very very
slightly modified structure,
this group of cells.
Here, the nephron cells are somewhat modified, these
are tall, these are dark looking, and these
cells love to taste the fluid here.These cells
are sensitive to, they are sensitive to sodium.
They are sodium sensors.
What is the function of these cells?
These are sodium sensing cells, right.
Now, actually these are pressure sensing system,
and this is sodium sensing system.
This system together make a whole apparatus.Now
look, afferent arteriole with polkissen and
this specialized group of cells from distal
convoluted tubule and its junction with the
proximal part, is that right?
This group of cell and this group of cell,
they make one specialized apparatus.
These acting as a baroreceptors, and these acting
as a chemoreceptors. These are the baroreceptors,
these are the chemoreceptors. They measure
the blood pressure, they measure the sodium
concentration, is that right? And they are
held together by some connective tissue cells.
They are held together by some, yes? Connective tissue
cells.
Now, I told you this blood pressure measuring
device, baroreceptor group it is called polcisin,
and this sodium sensing device which is present
in every nephron it has a special name.
You know what is the name of this special group
of cells which measure the sodium?
Thank God!
The researcher who found it, he did not put
his name on this. Actually in the beginning,
when researchers looked at the nephron structure,
they found this area was little bit more dark
as compared to the rest of the nephron.
These group of cells were more dark, so they
just call it Macula Densa, that there is some macule;
macule mean patch, patch of cell, which
is looking very dense, so this is called,
what is name of this thing?
Macula Densa.
Now, polkissen is from afferent arteriole, macula
densa is from distal convoluted tubule.
This is vascular component, this is nephron
component.
This is pressure measuring device, this is
sodium measuring device, and they are held
together through connective tissue cells which
are called Lacis Cell.
All this apparatus, as a group, all this apparatus
as a group is present in every nephron.
It means every nephron has blood pressure
measuring device, as well as sodium measuring
system. And as a group, polkissen plus macula
densa, they have given a very special name
to this and all of you know that name, what
is the name of this apparatus?
What's the name of this apparatus?
Ya!
Juxtaglomerular Apparatus.
Have you heard of it? So this is juxtaglomerular
apparatus.
Just they call it a special apparatus, right?
Juxtaposed to glomerulus, juxtaglomerulus, with
the glomerulus there is a very special apparatus.
Thank God they did not put a very complex
name for it!
They just say this special apparatus.
They never knew in the beginning what are
its functions, now they know.
Now, let's go back to our anology.
We were saying that person is bleeding, blood pressure is going down,
blood flow is going, yes, down. So blood flow is less,
baroreceptors are activated in juxtaglomerular apparatus and they release renin.
Meanwhile, when your blood flow is less, then
glomerular filtration is more or less?
Student: Less.
Less of course!
If there is less blood coming, right, then
filtration is also less.
Now you think really with your own cortex
that if filtration is very less, listen listen!
If filtration is very less, the fluid will
move through this lumen rapidly or slowly?
Student: Slowly.
Sure?
So whenever GFR is less, lumenal flow become
slow.
When movement of a fluid through the lumen
become slow then what happen?
These cells which are working on this lumenal
fluid, they have
more chance to work or less chance to work?
Student: Less.
More my friend, of course!
Look, if there are many mangoes going here,
attention Mr. Hadayat.
Let's suppose there is water going and a lot
of mangoes going here, and you're are sitting
here to catch the mangoes, if flow is very
fast you will miss the mangoes.
But what if it is very very slowly coming,
you will catch every mango, do you get it?
These cells work like you.
They are not catching mangoes there, they
are catching sodium there.
So when blood pressure become less, glomerular
filtrate become less,
lumenal flow become less.
These cells extract extraordinary amount of
sodium, and by the time the fluid, little fluid
reaches here, it is more then normal amount
of sodium or less than normal amount of sodium?
Student: Less.
Less than normal amount of sodium.
Then macula densa, it love to taste sodium.
So whenever GFR is less, then proximal part
of the nephron work on the slowly moving fluid,
extract too much sodium, so less sodium reach
to the sodium sensing device. And whenever
macula densa feel that less sodium coming, it become super active. It is activated when
there is less sodium reaching here and it
releases some, nitric oxide is released by
it and prostaglandins are released by it, and
they activate these polkissen cells.
Macula densa request this that please listen to us, there
is very little sodium coming here, there is
something wrong with GFR, probably blood is
not coming well, so please release more renin.
So renin release become further augmented. So,
now renin has been released under two influences,
under pressure change and under sodium change. So
every glomerulus has juxtaglomerular apparatus,
apparatus consist of blood pressure measuring device
and apparatus consist of sodium sensing device.
Blood pressure device is derived from the afferent
arteriole smooth muscle, sodium measuring
device is a derivative of nephron cells, together
they make juxtaglomerular apparatus.
Whenever blood flow is less to the kidney, right, this
apparatus releases excessive renin in the blood.
Now what this renin should do?
 Renin should correct the balance, bring the patient
out of tragedy. What was tragedy? Blood pressure
was going down and blood volume was going down.
Now function of renin is to bring the
blood pressure back as well as blood volume up,
so that patient does not die. For example
patient has lost one litre of blood and somehow
blood pressure should be maintained and somehow
blood volume should be maintained. We'll talk
about how renin does it, but before that we
will talk about one more factor. What is that?
That is, that whenever your blood pressure go down, whenever your blood pressure goes down, let's suppose
here is your heart, so what really happens, what is it? What is this? Carotid system, its carotid body.
What is the function of, sorry, carotid
sinus, not carotid body. This is what I am saying
is carotid sinus. Carotid sinus is another
blood pressure measuring device. It also has
baroreceptors. When patient is bleeding, the blood flow to here would be more or less? Less.
So whenever blood flow become less, this
carotid system is also activated and through
special neurons they report to the central
nervous system that blood pressure is falling.
They report to the central nervous system that blood pressure is falling. In the central nervous system,
right, okay. Let's forget about this part
of the diagram and concentrate only on this.
This is going into peritubular capillaries and then it collect back as venous, and okay connect it here,
this was renal arterial flow and this
is renal venous flow. Venous blood going back, right,
and arterial blood. Let's come back. I was saying
as soon as blood pressure goes down,
carotid sinus through the sinus nerves, right. This
is through the vagus, 9th nerve;
glossopharyngeal nerve, right. This message is given to central nervous system that blood pressure
is going down. As soon as central nervous system senses that blood pressure is going down, it will
stimulate the sympathetic outflow through
vasomotor center in the medulla. So, from the
medulla, fibers will come down,neuronal connections
will come down and stimulate what thing out?
Stimulate sympathetic outflow.This sympathetic outflow
which is going out, suppose these are preganglionic
sympathetic neurons and here are postganglionic
sympathetic neurons. I will not go to detail
of all sympthetic fibers. Right now we are concerned
only to those sympathetic fibers which are coming
to juxtaglomerular apparatus.These are sympathetic
neurons which are coming to juxtaglomerular
apparatus. Actually as soon as blood pressure
start going down, vasomotor center is stimulated,
lot of sympathetic outflow come. Some of the sympathetic fiber come to juxtaglomerular apparatus.
And what they will release there? They will release, neurons will release,
neurons will release norepinephrine, right. And these cells have receptor for norepinephrine.
These are beta-1 adrenergic receptor. What are these receptors? Beta-1 adrenergic receptor.
You must know there are beta-1 adrenergic receptor present on juxtaglomerular apparatus because
beta blockers block them also, and help us in hypertension management. They're beta-1 adrenergic
receptor present over here. So sympathetic outflow stimulate these beta-1 receptors and when
beta-1 receptors are stimulated here, more release of renin, according to Mr. Hadayat. Speculations.
More release of renin, so how many mechanism are there to release the renin from here? Number one,
two local and one systemic. Intrarenal mechanism is low blood pressure in the afferent arteriole and low
sodium concentration to the macula densa. Both
of them release renin. These two are intrarenal
mechanism of release of renin. Extrarenal
mechanism of release of renin is most important,
sympathetic fibers are connected with that, is that right? So we see this juxtaglomerular apparatus can
measure the pressure directly, can measure the sodium concentration directly and in every
emergency, whenever sympathetic nervous system will fire, renin will come. Now what this renin
will do? Let's see what this renin is going
to do? This renin is going to the general circulation.
From the renin, we'll go to the general circulation. Now
renin has come to the systemic circulation,
right, through the renal vein. Now what renin will do here? I told you renin is an enzyme, right.
And every enzyme work on special type of substrate
it will also work on some special type of substrate.
Before we go for that, you know liver has
lot of hepatocytes,
hepatocytes produce lot of protein normally.
You know they produce albumins and globulins; alpha globulins, beta globulins, but not gamma globulins,
because gamma globulins are immunoglobulins,
antibodies, which come from plasma cells,
B cells, but most of the proteins other than
gamma globulins, most not all, but most of
the proteins are produced by liver cells. Liver
cell produce a one very special type of protein
normally, and this protein is called angiotensinogen, angiotensinogen, right. Angiotensinogen,
okay I will write it in small way, This is angiotensinogen, right.
From where it is coming? It is coming
from liver. And it is not coming only during
crisis, it is produced by the liver all the
time. Right now all of you have in your blood
angiotensinogen. But as soon as renin come, it
will work on angiotensinogen, it will work
on angiotensinogen, and convert the angiotensinogen
into angiotensin-1, it is angiotensin-1.
So what is the function of Renin? Renin is an
enzyme which can convert angiotensinogen into
angiotensin-1. Is that right? Now, all of you
know it that when angiotensin-1 passes through
the lungs, it convert into angiotensin-2. That is the crux of understanding, that angiotensin-1
when it is passing through the lungs it convert
into angiotensin-2. It means in the lungs there
should be some enzyme which convert angiotensin-1
into angiotensin-2, and that enzyme is called
angiotensin converting enzyme. Again, when angiotensin-1 passes through the lungs
it convert into angiotensin-2. Angiotensin-2, right.
When angiotensin passes through the lungs, it convert
into angiotensin-2.This is large protein molecule.
It is decapeptide, I mean 10 amino acids. Then there is an enzyme in the lung which breakdown
two more amino acid and this product is octapeptide, only 8 amino acids.
I want to know one thing, angiotensin converting enzyme, on which so many drugs work,
angiotensin converting enzyme are present in which part of the lung?
Are they present in bronchioles? Are
they present in alveoli? Are they present in
capillaries? Are they present, where? Where in
the lung angiotensin converting enzyme is present?
All of you know that many drugs which
inhibit that enzyme.
We must know where is that enzyme? Yes, we talk to Abbas. No idea?
Jaime? same?
Yes, Hadayatullah?
You are with the majority or you'll try to
guess something? In the lungs, everyone has
heard there's enzyme called angiotensin converting
enzyme. Have you heard of it or not?
MashaAllah you've heard of it.
Where exactly it is present? No idea? No idea? Jaime? Just guess it, wild guess.You don't want to even
guess? Maybe it is present on the pleura. Yes, any
wild guess. Alveoli. What do you think?
Pneumocytes. Okay, write it down on the book
and put a very big cross on this.
You know why? If it is present in alveoli, then
tell me one thing it means your blood has
to pass through alveoli. Alveoli are blood
flow system or air flow system? They are air
pockets or blood pockets? Yes? No, they are? Alveoli
are air pockets and pulmonary capillaries
are attached with them but pulmonary capillaries
are not alveoli themselves, right. So one thing
is sure alveoli should not have the enzyme
otherwise there will be tragedy, blood has
to jump into alveoli, so that angiotensin-1 should
convert into angiotensin-2. Okay let me explain. Actually
here is alveoli. Let's suppose this is airway
and these are, suppose alveolar system .
These are air pockets.
Of course, blood should not enter there, is
that right?
Actually, you know on the endothelial cells,
 what are these?
Endothelial cells of pulmonary capillaries
beds.
On the endothelial cells, there is a unique
enzyme expressed.
This enzyme is expressed on the surface of
endothelial cells, that is why this enzyme
is called ectoenzyme, because this is not
intracellular enzyme, this cell is expressed
on the surface of endothelial cells, right,
not release into blood.
But now they believe that not only pulmonary
capillaries have capacity to convert angiotensin-1 into 2,
even some other capillaries
beds can also do this function.
But for your level you just remember that
in the pulmonary capillary endothelial lining,
they are expressing enzyme called, what is
the name of these enzymes?
You know they are very angry because you don't
remember where they are, look at their expression,
right.
These are which enzymes?
Angiotensin Converting Enzyme.
What they are doing?
Actually, they are responsible to convert angiotensin-1
into angiotensin-2, this is a function of
these enzymes. These are the function of these
enzymes which are called angiotensin converting
enzymes, that they convert angiotensin-1 into
angiotensin-2.
And when we talk about the drugs like Captopril,
Enalapril, Lisinopril or other angiotensin
converting enzyme inhibitors, those drugs basically
bind with these proteins and block their function.
Or we say there are whole group of drugs called
angiotensin converting enzyme inhibitors.
What is the function of those drugs?
These drugs are basically bind with these
enzymes and blocking their action.
Every doctor knows that these enzymes are
converting angiotensin-1 into angiotensin-2,
but some good doctors know they do also one
more function.
What is the second function of this enzyme?
There is another product in the blood which
is called Bradykinin. There is another product
in the blood which is called Bradykinin.
Bradykinin is broken down by these enzymes, bradykinin, they don't look at it because it is inactivated,
bradykinin inactivation.
Bradykinin is vasodilator, and angiotensin-2
is vasoconstrictor.
So what is the function of this enzyme?
These enzymes break down the vasodilators
and produce vasoconstrictor.
Of course on blood vessels will constrict,
blood pressure will go up, am I clear?
Now, so again let's recap up to this, patient
was actively bleeding, right, you could take
some time, renal perfusion is reduced, then
angio, your what is this? blood pressure
sensitive cells release renin, plus macula
densa senses low sodium coming here, a sign
of low GFR that also forces this cell to release
renin.
Moreover, falling blood pressure activate
the sympathetic outflow and sympathetic fibers
coming to the juxtaglomerular apparatus, further
release of renin.
This renin is an enzyme which come into general
circulation and break down the angiotensinogen
into angiotensin-1.
And when angiotensin-1 is passing through
the, mainly, when it is passing through the
pulmonary circulation then angiotensin converting
enzymes, which are normally express on the
endothelial cells of pulmonary
circulation, they convert angiotensin-1 into
angiotensin-2.
So they produce very powerful vasoconstrictor,
and of course these enzymes are very active,
very intelligent, while they're producing
vasoconstrictor, they don't forget to inactivate
vasodilators like bradykinin.
Now we'll have the angiotensin-2 in our circulation.
Now we have to see what angiotensin-2 will
do in the body?
What it should do?
It should bring blood pressure up and blood
volume up, that was the problem naa.
So now we see how angiotensin-2 is going to
achieve its function.
Let's come to the actions of angiotensin-2. First
we'll talk about the classical action.
Number one, angiotensin-2, okay I will draw here circulatory system in a little detail;
left heart and these are the arterioles. From
the aorta these are the arterioles, and here
is your right heart, this is a venous system.
And of course in between these arteriovenous
system there are, what are these?
Capillary beds, I hope you must know.
Blood come from arterial side, passes through the capillary beds,
and then it is drain to the venous side, right.
This is right heart and that is left heart,
and of course, you will not forget to draw that
there must be lung over there, that this your
pulmonary circulation, and blood gets oxygenated
over there and then it comes to the left atrium,
and of course here is your, what is this?
Air spaces, clear?
Now we'll see first of all what is the action
of angiotensin-2 on this system, because pressure
and volume is falling into this system.
First of all, angiotensin-2 has receptors
on the arteriolar smooth muscles, what are these?
Arteriolar smooth muscle, angiotensin-2 receptors
are present on arteriolar smooth muscle.
Plus, angiotensin-2 receptors are also present
on the venular smooth muscle, so they are also
present over here, right.
Now what really happens; number one, angiotensin-2
will work on, what is this? Venous smooth muscle,
and angiotensin-2 act on the angiotensin-2
receptors on venous smooth muscle, veins constrict.
When veins will constrict, can blood remain
pool into vein?
No.
Most of our blood is normally present in the
veins, veins contain about 70% of total blood
volume, that is why we call them the vascular
component with highest capacity, or simply
these are called capacitance vessels.
So angiotensin-2 will constrict the veins.
When veins are squeezing, pressure in veins
will go up and blood will rush towards, where?
Where the blood is going? To the heart and then to the, eventually left heart.
So under venoconstriction, blood going
to the left heart is, less or more?
When you squeeze the vein, venous return
to the heart is increased.
Now listen, when blood flow increases to the
left heart, it mean cardiac filling is, more.
So venous return, venoconstriction,
lead to increase venous return that lead to
increase cardiac filling, increase cardiac
filling lead to increase end diastolic volume
and increased end diastolic pressure. The
end of the diastole, volume and pressure
is more in the ventricle, so ventricle is
stretched, and according to Frank Starling Law,
more you stretch the ventricle, more
it contract.
Frank Starling law is stated that within
physiological limit, more you stretch the
myocardial cell, more they contract, of course
within physiological limit,
don't rupture them, right.
Now, so whenever venous return is more, end
diastolic volume is more, we say that preload
on the heart is more, and whenever preload
on the heart is more; preload is the amount
of blood in the ventricle on which it has
to produce contraction, is that right?
So, then whenever there is more blood accumulated here, more it is stretched,
more it contract, so stroke volume will become more.
So that will lead to increase stroke volume,
that will lead to increased stroke volume.
And of course when stroke volume is more, then
what is there?
Increased cardiac output, and when there is
increased cardiac output, that will lead to
increase in systolic blood pressure. That
was the point we wanted to reach.
You know our systolic blood pressure was falling,
as well as diastolic blood pressure was falling,
and your bleeding was going on, for example
bleeding was from here,
so blood pressure was falling.
So by venoconstriction, and increasing in
the venous return to the heart, and increasing
the end diastolic volume, and of course increasing
the contractility and increasing the stroke
volume, resulting into increase cardiac output
eventually increases systolic blood pressure,
because systolic blood pressure mainly depends
on cardiac output, am I clear?
During the systole blood pressure will
go up. Meanwhile, angiotensin-2 will also work
on, what is this?
Arterial smooth muscle, and arterioles will
constrict. Now, if arterioles will become very
narrow, during the systole when lot of blood come
here, can it easily move to that side?
No. So even if heart is not pumping because
after systole, heart will undergo relaxation. There
will be be onset of diastole. During the
diastole, of course, aortic valve closes,
blood cannot go back.
The only choice for the blood during diastole
was that no blood was coming during the diastole here,
but whatever blood is pumped here, that should
rush to the capillary side and venous side,
during the diastole.
Now, if arterioles are open too much, most of
blood will run forward, and pressure in the
diastole will fall. But if arterioles are
too narrow, they're tight, do you think blood
is present during the diastole here can
it easily move?
So blood will be retained on the arterial
side, and pressure in the arterial tree
during the diastole will be also increase,
and we'll say that diastolic blood pressure increase.
There is increase in diastolic blood pressure.
So that was our target, what was the target?
That when we were losing the blood, systolic
and diastolic blood pressure were going down,
by increasing the venoconstriction, and venous
return will increase the cardiac output and
systolic blood pressure.
By increasing the arteriolar constriction,
we reduce the movement of blood from arterial
side to the venous side, and blood which is
trapped here, even during diastole it maintain the
pressure up,is it right?
The story is not yet over.
Meanwhile, angiotensin-2 will also go to cells
here and these cells in the outer,
what is this?
Zona Glomerulosa, these are the cells in outer
adrenal cortex, these cells are called zona
glomerulosa, and what are receptors here?
 These cells also have receptors which are receptors
for angiotensin-2. When angiotensin-2 work
here, what happens?
When angiotensin-2 work over here, these cells
start releasing a substance called Aldosterone.
Angiotensin-2 will act on zona glomerulosa
and lead to the release of aldosterone.
What this aldosterone will do? This aldosterone,
now let's see how aldosterone work.
Okay I will draw just one cell here, this
is one cell I have enlarged and this cell is
called Principal cell or P-cells in last part
of nephron, usually they are in the second
half of the distal convoluted tubules and they
are present in collecting tubules,
what are these cells? Principal cells.
Actually this is, let's suppose the nucleus of
principal cell. It has different genes here, of course
every nucleus has genes. Now listen, what aldosterone
will do? This aldosterone
which is released by, from where?
Zona glomerulosa, it will come into circulation
through the circulation, it will reach to
the P- cells, and what it will do? This aldosterone
will come here, let's suppose this is the aldosterone.
When aldosterone enter into this cell, there
it will find the receptors for aldosterone,
and let's suppose this is the receptor for aldosterone. So
this is a very special type of protein which
act like a key, and this key is operated by
which substance? Aldosterone.
This is aldosterone operated receptors, 
 what they do?
As soon as aldosterone bind, this protein
rush to the nucleus, and open the locks of
the genes, what it is going to do? Open the
locks of the genes.
When gene number one is opened by this aldosterone
receptor complex, gene number one start making
a special type of protein, and that protein
is planted into basolateral membrane.
What is this? Basal side and lateral side of which
cells? Principal cells.
So these special proteins are planted into
basolateral membrane, under the direction
of aldosterone.
What these proteins are doing? Are they doing
anything important or just  Paris fashion? Ya.
What these proteins are doing? These are 
 sodium-potassium ATPases.
They are present in every cell.
But in this kidney cell they are present on basolateral membrane, and not present on luminal membrane.
But under the direction of aldosterone, the
concentration of sodium-potassium ATPases on
the basolateral membrane has been increased.
So what really happens, that these cells,
these are sodium-potassium pump, so they keep
on throwing the sodium from the cell to extracellular
environment, so cell start throwing the sodium
from its cytoplasm to the blood. And at the
same time, you must be knowing they are accumulating
in the cell, what is this? Potassium, these
are sodium-potassium pumps, so it means under
the influence of aldosterone, principal cell
start throwing the sodium from their cytosole
to the interstitium, and start accumulating
potassium. So these cells become extremely
poor in sodium, and extremely rich in potassium,
under the directions of aldosterone mediated
enhanced sodium-potassium ATPases.
Then gene number two is also activated by
the same, gene number two is also activated
by the same receptor system, aldosterone receptor.
When second gene is stimulated, this produces the product which will not go to the
basolateral membrane, which will, product
will come and it will be planted into,
what is this? Luminal membrane.This special protein,
which is product of the second gene, this protein
fits into luminal side. And what is this protein? This
is sodium channels, these are not pumps, these
are simply channels.They let the sodium pass
freely as sodium want to go. Now, whatever
little amount of sodium will come here, if
the cell is extremely poor in sodium, sodium
will rush in, you know things move from high
concentration to low concentration. As soon
as sodium come in, through the pump it is thrown
to the blood.
This is how sodium is reabsorbed  under the
direction of aldosterone, and aldosterone
first enhances the activity of the sodium-potassium
ATPases, so the cells keep on pushing too much
sodium from the cells to the blood, cells become
extremely poor in sodium.Then sodium automatically
start shifting from the, what is this?
Nephron lumen to the cell and from the cell
to the blood, is that right? So that sodium
which was about to be lost into urine is reabsorbed, and
you know who loves to follow sodium? Who loves
to follow sodium? I think its water, right.
So naturally sodium is reabsorbed along with
that water is also reabsorbed. And of course,
cell was rich in Potassium. So third gene is
activated and third gene make potassium channels,
and potassium is more inside the cell or in the
lumen?
Inside the cell, even he knows. Good. So what
will happen, potassium will start leaking out. So
under the direction of, what, under the direction
of aldosterone, principal cells start reabsorbing
sodium and water to the blood, and start secreting
the extra potassium into urine. Is that right?
Now, this salt and water, this salt and water, or
you can say simply sodium and water, which
is retained in the blood, they will decrease
the blood volume or increase the blood volume?
So its very easy, if blood volume is increased,
if blood volume is increased then, venous return will,
yes, increase. So cardiac ventricular fillings
will increase. Ventricular contractility will
increase, and systolic blood pressure will
go up. This is how aldosterone, the retaining
salt and water take the systolic blood pressure
up. Another support to that, angiotensin-2 has
done this work through the aldo. Now angiotensin-2
will, angiotensin-2 will go to the central
nervous system, I think its a long travel, and it will work on receptors present in the hypothalamus. Angiotensin-2
will go and work with the receptors on hypothalamus,
and force some neurons in hypothalamus and
they will activate action potential which
will reach to the posterior pituitary, and
from there what will come out?
Don't tell me any funny thing. What will come
out from posterior pituitary?
ADH, don't tell me oxytocin, that is not going
to help the patient right now, right.
So, now angiotensin-2 has built a long travel
going to the hypothalamus, stimulate which nucleus?
Angiotensin-2? ADH?
Supraoptic nuclei, excellent!
Supraoptic nuclei are stimulated and eventually
the supraoptic nuclei have their nerve endings
in posterior pituitary, still, and from there
ADH come into blood. What ADH will do?
I will not go into details. Just trust me, I
am right.
What ADH will do, it will make the last part
of the nephron more permeable to water. It
will under the direction of ADH, right, the
cells of last part of the nephron become more
permeable to water. Is that right? And you know
that last part of the nephron is going to
medulla of the kidney. Is that right? And when this nephron is
moving towards medullary interstitium, 
 medullary interstitium is hyperosmolar.
Do you know that or not? When I will teach you kidney you will
know that very clearly, that medullary interstitium
is hypersomolar. Osmolality here is very high. When
this part of the nephron become water permeable, here
fluid is hypoosmolar ,here fluid is hyperosmolar. Water
will move from hypoosmolar area, it will be
pulled to hypersomolar area. So water will
rush from, where? Yes, from the last part of
the nephron from the lumen, water will rush
through the cells to the interstitium. So there
will be increased water reabsorption so that
water should not be lost into urine. Is that
right? And this water which is coming back
its too easy to understand. This water will increase blood volume, increase venous return, of course,
increase cardiac filling, increase contractility, increase
stroke volume, increase cardiac output, increase
systolic blood pressure. Again we reach to
the blood pressure, it again raise the blood
pressure. Is that right? Am I clear?
Any other function of Angiotensin-2? Extremely
important function of angiotensin-2 yet not
mentioned is, it is a super stimulator of sympathetic
nervous system.
This is a super stimulator of sympathetic
nervous system. So angiotensin-2 receptors
are present even lot of component of sympathetic
nervous system. So what really happens,
look here, central sympathetic outflow will increase, number one.Then these cells in the ganglia, sympathetic
ganglia, they are also stimulated. First, central
sympathetic outflow is stimulated, then these
ganglia are stimulated.Then, if this is the
postgangloinic nerve ending, let's suppose this
is the target tissue, on which this nerve ending
is ending.This target tissue may be venous
smooth muscle, this may be arteriolar smooth
muscle, or this target tissue may be myocardium.
Normally, what happen that postganglonic sympathetic
nerve endings release norepinephrine. Norepinephrine
work on the receptors, and once norepinephrine
which is released has done this action on
the receptor, 80% of it is taken back by the
nerve endings. Is that right? This is normal
physiology. Now what angiotensin will do here, angiotensin-2 has receptors here also. It will stimulate
the nerve ending in such a fashion, the release
of norepinphrine will be increased. And reuptake
of the norepinephrine will be reduced. So amount
of norepinephrine which is present in this
area is reduced or increased? If nerve ending
is producing more norepinephrine, if nerve
ending under the direction of angiotensin-2
is releasing more norepinephrine, and not recapturing it,
then amount of norepinephrine present in
the synapse is less or more? It is more. If
you are releasing something more, and not taking
it back, so then that thing will be there less
or more? You know it. So in this way norepinephrine
will be more in this area and even angiotensin-2
has receptors which increase the adrenergic
receptor concentration on the target tissue.
So it means what now angiotensin-2 is doing, it
is increasing the whole parameters of sympathetic
nervous system ,increasing the sympathetic, central
sympathetic outflow, increasing stimulation
of sympathetic ganglion, increased stimulation of sympathetic nerve endings, increased responsiveness
of target tissue. We'll see what will happen
with this. Look, if sympathetic nervous system
works more on the veins, veins will constrict.When
they will constrict further, more increase
in venous return; now you must tell me, more
cardiac filling, more contractility, more cardiac
output, and more stroke volume. Sorry, more increase
in systolic blood pressure, right, because
venocontriction. Meanwhile, when sympathetic activity
is increased on the arterioles, more arteriolar
constriction and increase in diastolic blood
pressure. When sympathetic activity increase
and releases more norepinephrine here, more
release of renin, whole system is amplified.
Is that right?
And then we should not forget something very
important. Angiotensin-2 has receptors on the
central thirst system. So when angiotensin-2
work on the, those group of neurons which
control the feeling of thirst, patient who is
bleeding he will feel thirsty. Of course he
will ask water, and if you have it he will
take the water and try to increase blood volume, again
that is helpful. By all these means, what angiotensin-2,    I must say by all these means, Renin Angiotensin
Aldosterone Axis, what it is doing? It is trying
to elevate the blood volume and blood pressure.
Is that right? Am I clear to everyone? No problem?
This is physiological functions of angiotensin-2
and aldosterone. But one most important pathological
function I did not tell you.There are some
diseases in which blood flow to kidney is
chronically low. For example, if you have congestive
cardiac failure, if you have a cardiac failure, heart
has a very poor cardiac output. For example
I have very severe heart failure, my systolic
function or contractility of the ventricles
is very poor, whatever the reason, if my heart
is a poor pump, my blood flow to every organ
is reduced, including blood flow to kidney
is reduced. So all those patients in which
heart fail as a pump, cardiac output become
less then blood flow even to the kidney is
reduced. And in these patients, there is chronic
activation of renin angiotensin aldosterone
axis.You understand it? In the same way, who
as person has cardiac failure, of course his
blood pressure also drops, so sympathetic stimulation
is also chronically activated. So patient who
have congestive cardiac failure, right, in them
there is chronic sympathetic activation and
there is chronic renin angiotensin aldosterone
activity. When angiotensin-2 level is chronically
increased then something really very bad happen.
What happen? If angiotensin-2 is chronically increased, and aldosterone is chronically increased, this
chronically increased angiotensin-2, right, and
aldosterone will work on the myocardium, and
change the morphology of the heart. This is
something which is recently discovered, but
very very important. The patient with congestive
cardiac failure have chronic elevation of
angiotensin-2 and aldosterone, and they chronically
work on the myocardial cell and fibroblast
there. They stimulate the proto-oncogenes, genes
which are concerned with growth.These all
myocardial cells start producing growth factors. If
myocardial cells start producing growth factor
and these growth factors which are produced by the myocardium work on the myocardial cells,so myocardial
cells undergo hypertrophy. But it is not normal
hypertrophy, it is pathological hypertrophy. At
the same time myocardial cells and fibroblast
start producing extra amount of connective
tissue. So myocardial cells become abnormal, abnormally enlarged, and in between the myocardial cell
lot of fibrotic tissue and extracellular
matrix is deposited, and these things under
chronic influences, these things under chronic
influences lead to alteration in geometry
of the heart. Chronically elevated aldosterone
levels and chronically activated angiotensin-2
levels in congestive cardiac failure lead
to morphological changes in the heart.
What are these morphological changes? Myocardial  cells undergo pathological hypertrophy, and they
undergo pathological production of extracellular matrix and growth factors and many other alterations. Those
all alterations in a lump, lump sum, they are
called cardiac remodeling. So we can say in
congestive cardiac failure due to chronically
elevation of angiotensin-2 and aldosterone
myocardium undergo progressive pathological
geometrical changes, or we simply call it as
Dr.Rao said it, we simply call it myocardium
is undergoing remodeling phenomenon. This chronic
remodeling of myocardium makes a myocardium
more poor contractile machinery, and patient
with congestive cardiac failure under the
chronic influences of angiotensin-2 and aldosterone
go under progressive cardiac failure. Is that
right? In the same way, chronically elevated
angiotensin-2 and aldosterone also work on
the smooth muscles of the vessels, and bring
pathological changes in them. So, this is one
of the most modern concept that if you allow
the renin angiotensin aldosterone axis to
work pathologically high, that will eventually
disturb the whole efficient geometry of the
heart and well as vasculopathies are produced.
Is that right? That is why any patient with congestive
cardiac failure at any stage that comes to
you, either at very early stage or late stage, most
important drug is drug which inhibit the angiotensin
converting enzyme, so that angiotensin-2 should
not be produced and aldosterone should not
be released. Or alternatively, we use the drugs
which block the receptors of angiotensin-2. So
that angiotensin-2 blocking, receptor blocking
drugs are also very effective, and not only
they change the preload and afterload and blood
volume but they also reduce the pathological
progressive geometrical changes in the heart, they
prevent the cardiac remodeling. We'll discuss
in detail what are these drugs and how they
work in the next session.
