Renin-Angiotensin-Aldosterone System (The RAAS)

Renin-Angiotensin-Aldosterone System (The RAAS)

August 30, 2019 30 By Bertrand Dibbert


>>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. Thank you so much for visiting
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