>> Hello and welcome to the Penguin Prof Channel.
In today's episode we're going to look
at this beast the renin-angiotensin-aldosterone
system.
People try and memorize this.
Oh my goodness, don't do it.
We're going to do it Penguin Prof style so you understand it
and don't have to memorize it.
If you find these videos helpful could you please help me
out by just taking second and clicking those buttons below,
it makes a big difference.
Thanks. You want to stay tuned to answer these questions.
What is the RAAS?
What does it do?
Who's involved?
Who are the players?
And how do those [beep] inhibitors work?
You'll find these on a lot of exams and I have to admit,
it can be a little bit overwhelming.
The good news is that actually if you understand the pathways,
the names of all of these groups of drugs actually make sense.
So that is what we're going to do today.
What you should know already some basic anatomy
and physiology of the kidney and the nephron in particular,
as well as homeostasis, negative feedback loops and the world
of signal transduction.
And of course, I will put links to these videos down there.
Just to make sure we're all
on the same page we have the terms ligand and receptor.
The ligand is the thing that binds
and we use this symbol here for an inhibitor
of that ligand receptor binding, so it's some sort
of antagonist for example.
This can be found at the surface of a cell,
it can also be found inside the cell, in the cytoplasm
or even in the nucleus.
Today we're going to take a look at aldosterone
which is a steroid hormone
and its receptors are in the cytoplasm.
And you can block this reaction between aldosterone
and the aldosterone receptor
with an aldosterone receptor antagonist
like this drug spironolactone.
So we show that with this symbol here.
So I want to make sure that is clear.
All right, let's get started.
What is the RAAS?
It is the renin-angiotensin-aldosterone
system, you can see why an acronym is needed.
It's an endocrine pathway, it regulates fluid balance.
We're talking about all kinds of extracellular fluids all
over the body, the blood plasma, the lymph, interstitial fluid
and also arterial vasoconstriction.
So it is a major player in regulating blood pressure.
When the RAAS system is activated you get increased
fluid retention, as well as vasoconstriction and both
of those things will increase blood pressure.
And this is problematic for patients who are dealing
with hypertension, heart disease, renal disease,
complications due to diabetes, etcetera.
Many different drugs affect various aspects of this system
and we're going to go through those
and understand how you can sort of take
out different steps along the pathway and collectively,
these drugs are going to lower blood pressure
and reduce stress on the heart.
The players in this system include --
there's a lot, the kidney, the liver, the lung believe it
or not, and the adrenal cortex.
And we've got some more too, we've got the pituitary gland,
the hypothalamus and the heart
and the cardiovascular system as a whole.
So as you can see, there's a lot of players here.
Extrinsic activation of this system is going to come
from a detection of low blood volume
or dropping blood pressure and this could be due
to severe dehydration,
hemorrhage those sorts of things.
We have intrinsic regulation too that is to say,
the nephrons themselves activate this system and we're going
to look specifically at the renal corpuscle.
So that is the glomerulus, the afferent
and efferent arterials leading in and out of it
and the glomerular or the Bowman's capsule.
So quick review of those parts right here.
The region we're really interested is right here the
juxtaglomerular apparatus.
So you want to notice the afferent arterial,
this is the efferent arterial
and this is the distal convoluted tubule
cutting cross-section.
And you want to notice these little green jobbers here,
these are granular juxtaglomerular cells
or just granular cells and they're going
to produce the enzyme renin and it's important
to notice how close together all of these structures are.
In particular, the distal convoluted tubule is very,
very close to the afferent arterial
and there's some specialized cells right here called the
macula dense that are going to be really important.
They sense what is going on in the filtrate, in the lumen
of the distal tubule and they can send a message
to those granular cells to help activate the RAAS system.
The intrinsic RAAS activation can come
from beta-1 adrenergic stimulation,
so that's from the autonomic nervous system.
A decrease in renal perfusion, we call this hypoperfusion
and the granular cells themselves sense that.
So they can sense the volume change
of the blood going in and out.
And a decrease in sodium chloride in the distal tubule
that is sensed by the macula densa.
So what's happening is the macula densa these cells right
here are able to sense the sodium chloride concentration
of the filtrate.
And a drop in sodium chloride concentration is usually due
to low filtrate volume.
So if there's not enough filtrate going
through at any given time, then you have more time
for reabsorption of sodium chloride.
That's what's going to cause that drop.
So any of these three things will cause the RAAS activation
to occur.
And what's going to happen is those granular cells will
secrete the enzyme renin, which is also known
as angiotensinogenase.
I'm just going to call renin if that's okay for you.
It is an enzyme, it is not a hormone.
A lot of students mess up with that.
There are no peripheral receptors for renin
and it is an enzyme, it catalyzes a reaction.
We're going to see that reaction right now.
So the liver is where we start
and it produces a protein called angiotensinogen.
It's 453 amino acids long,
but the first 12 amino acids are the ones
that we are interested in.
Oh look, there they are.
Now angiotensinogen is produced all the time
and released constantly by the liver and floats
around in the body, but it is completely inactive.
However, if it runs into the enzyme renin produced
by those granular cells there is a hydrolysis
between these two amino acids shown here
and what you get is a decapeptide called
angiotensin I.
Angiotensin 1 is also not biologically active,
so now it's flowing around all over the place and it has
to be activated by an enzyme that is found primarily
in the surface of pulmonary epithelia and also
in renal tissue and other places as we're finding out now.
This enzyme is called an angiotensin-converting enzyme,
doesn't that makes sense?
We call it ACE for short.
So when angiotensin I as it flows around the body passes
through the pulmonary capillaries and it meets
up with the ACE enzyme, then you get the final cleavage here
that converts angiotensin I
to the active hormone angiotensin II.
And angiotensin II will then be available to bind
to AT receptors as they're called,
which are found throughout the body.
These are primarily G-protein coupled receptors
and they're going to cause a lot of different effects.
There's actually four different types.
The important thing is what angiotensin II does.
Angiotensin II causes systemic vasoconstriction of arterials.
That in and of itself increases blood pressure.
We're going to get stimulation of the sympathetic division,
so you're going to get things like an increase
in both heart rate and stroke volume.
That of course, will also increase blood pressure.
You're going to get vasoconstriction of the afferent
and to a lesser extent efferent arterioles in the nephron,
that's going to keep the pressure in the glomerulus high.
We're going to get decreased blood flow
to the nephron peritublar capillaries.
Some of you may know those as the vasa recta.
And so if you decrease the blood flow there and so
if you decrease the blood flow there then you're going
to get reduced washout as it's called of the ions,
primarily sodium, chlorine and urea
and increased sodium reabsorption in nephrons overall
and that's going to be due to a stimulation
of sodium proton exchangers.
In addition, the adrenal cortex is going to be stimulated
by angiotensin II to release the steroid aldosterone.
And aldosterone is going to have an effect in the nephrons
as well, you're going to get an increase of ion
and water reabsorption.
So again, all of these ions and water reabsorption is going
to act to increase fluid of course and ion retention
and increase the blood pressure.
And finally, we're going to have the release
of vasopressin or ADH.
This is a hormone that is made in the hypothalamus, it's stored
and released by the posterior pituitary gland.
And what vasopressin does is it acts on the cells
of the collecting ducts and it causes water to be reabsorbed
and it also stimulates thirst.
If you want to see more about that in particular
and actually how that happens
and these really cool little guys called aquaporins you want
to click on this little link and check it out below.
The easiest way to get around this is to go
through the whole process from start to finish
and we'll put it altogether.
So we're going to start with the liver and the release
of that protein angiotensinogen.
And again, that is not biologically active,
it will combine with the enzyme renin made
by those granular cells
and angiotensinogen will be converted to angiotensin 1.
Again, not biologically active, but it will flow around the body
and it will come into contact
with that angiotensin-converting enzyme found primarily
in pulmonary capillaries, but also elsewhere
and that enzyme will convert angiotensin I to angiotensin II.
That is the active hormone which is going
to cause a whole variety of effects, increase of activity
in the sympathetic division of the autonomic nervous system,
an increase in the reabsorption of all kinds of water
and ions in the nephron.
They're going to get a stimulation
of aldosterone secretion by the adrenal glands,
arterial vasoconstriction throughout the body
and you are going to get the release of vasopressin or ADH
from the posterior pituitary and that will act
to cause water retention or water reabsorption
in the collecting duct.
Oh my goodness I know, all these things together,
all of these effects of angiotensin II if you look
at them they all act to retain water and ions
and that will cause blood pressure to increase and all
of these things will feedback natively on the cells
that are producing renin in the kidney.
So that's the negative feedback loop
and this is the entire loop.
If you can kind of get your head around you're going to be able
to answer most questions about the RAAS system from an overview
like this and clinical applications will make a lot
more sense.
So we have four major groups of drugs that we can use
to inhibit this system,
aldosterone receptor antagonists,
direct renin inhibitors, ACE inhibitors and ARBs or Sartans.
So we're going to go through all of these and you're going to see
that the secret's in the name.
So if you understand the pathway,
then these names will make sense
and then how the drugs work will also make sense.
Let's look first
at the aldosterone receptor antagonists.
So right away you should be able
to tell what these things are going to do.
You may see them
as antimineralocorticoids aldosterone is called a
mineralocorticoid
and so sometimes you'll see the receptors referred
to as mineralocorticoid receptors.
And that's really the trickiest part
of this thing if you ask me.
These are intracellular receptors right,
aldosterone is a steroid.
They are called potassium sparing diuretics
and hopefully you can see why.
So for example, spironolactone it's the most common one,
so I have the trade names here in parentheses.
This is an antagonist, it blocks aldosterone from binding
to those receptors so it will prevent aldosterone
from causing these effects.
Now direct renin inhibitors this kind of makes the most sense,
it's the most obvious way to limit the RAAS system,
it's like we'll just kill it at step one.
Interestingly enough, researchers have been working
since the 70's to develop a direct renin inhibitor
that has oral bioavailability.
It turned out to be difficult, there's really one on the market
as of the making of this tutorial, it was approved
in 2007, it is still the only one available
and it blocks the production of renin.
ACE inhibitors, these are much more common
and there are many more of them.
So if you block the conversion of angiotensin I
to angiotensin II, then you don't allow the production
of the active hormone.
Here are some common ACE inhibitors and you can see
if you block that enzyme you're not going to get the conversion.
And finally, there are angiotensin II
receptor antagonists.
They are sometimes called angiotensin receptor blockers,
ARBs or Sartans and they prevent angiotensin II from binding
to their receptors, thus preventing their effects.
So finally, this slide is a summary
of all the options for inhibition.
We can inhibit the effects of aldosterone
by using aldosterone receptor antagonists.
We can inhibit the production of renin.
We can inhibit the production
of the angiotensin-converting enzyme
or we can inhibit the actions of angiotensin II
on their receptors throughout the body.
So what I hope you can see here is
that by understanding the different parts of a pathway,
it's very easy then
to understand how various drugs will work
and hopefully it becomes something very different
than just a memorization exercise.
As always, I hope that was helpful.
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