Now you have this really cool diagram in your notes.
I want you to take a look at it, it shows you where all the players of the RAAS -
what organs they come from, what comes from the liver,
what comes in from the juxtaglomerular cells, what comes from the lungs,
what happens in the capillaries, and what happens, it's really neat.
So, I want you to pause the video for a second, just take a look at it,
orient yourself to that picture and then restart the video when you are ready.
Now, let's break the RAAS down very simply.
Okay, some reason your body senses, wow, we need to raise the blood pressure.
Maybe it senses a drop in the blood pressure, maybe it senses a low sodium,
whenever that alarm bell goes off the juxtaglomerular cell in the kidneys
now, you may not be proud of me for saying that but that word scares me to death every time I have to say it,
juxtaglomerular cells, so I'm pretty impressed that I got it out.
But renin is excreted from these J cells in the kidney because why?
The body sensed a need to raise blood pressure so that's why renin,
that's squirted out through your kidneys.
Now, renin connects up with circulating angiotensinogen.
When you're looking at your downloadable section where does angiotensinogen come from?
What liver colored organ does angiotensinogen comes from?
When renin and the circulating angiotensinogen meet up, you end up with a different product angiotensin I.
Okay, so I went from renin to circulating angiotensinogen.
Why did the renin appear?
Because my body sensed I needed to raise my blood pressure
so renin connected to the circulating angiotensinogen, I end up with angiotensin I.
Now, when angiotensin I meets ACE or angiotensin converting enzyme,
you end up with angiotensin II, this is another bad mama jama
this causes potent vasoconstriction and volume expansion
so the RAAS is a system one of the five key players that my body uses to maintain blood pressure.
The renin, can you remember the reason that renin appears? Why does the body put that out?
Why do those J cells in the kidney put out renin?
Renin connects with angiotensinogen, then you end up with angiotensin I,
angiotensin I hits ACE, angiotensin converting enzyme, pretty cool name, right?
And you end up with angiotensin II.
The end result of angiotensin II, my blood pressure is raised two ways
with the potent vasoconstriction and volume expansion so what does that mean?
That reminds me of that little girl in Willy Wonka, remember, when she said, "I wanted to go,
she was the blueberry girl and she, that volume blue ride up“
so, that's why I use that to remind you.
So look at the break down at the bottom of your screen.
Why are we going over this over and over again?
Because that's a great study tip for you, repetition really helps your brain remember things.
It likes to see things that it's familiar.
So renin plus angiotensinogen equals angiotensin I,
then angiotensin I connects with ACE and you end up with angiotensin II.
Now there's two ways the release of angiotensin II raises your blood pressure.
Can you remember the two ways, and you don't have to do the sounds effects
but remember the two ways that angiotensin II raises your blood pressure.
Okay, so we're not done with this.
We're gonna keep going over and over this concept
because this is the key to understanding multiple high blood pressure medications,
okay, just understanding how the RAAS works will make it
so much easier for you to understand these types of medications.
So the two reasons that your blood pressure elevates
because of the end product of RAAS angiotensin II are volume expansion and vasoconstriction.
Now, you know the sound effects that go with that, right? Vasoconstriction and volume expansion.
Now the volume expansion comes from aldosterone, the adrenal gland releases aldosterone.
Now, why would I say it like that? Because most normal people don't say aldosterone“
one, it's pretty annoying and two it's something you didn't expect and will help it stick in your brain better,
so while you don't have to agree with the way things I do things,
anything you can do while you're studying that makes something stick in your mind,
then you'll say, aldosterone, I'll remember that.
I can be in the mall and I'll meet somebody who I had ten years ago in pharmacology
and they'll say, hey, Prof. Lawes, aldosterone, and I think, yes!
So anything that's weird or unexpected that helps you remember information, go with it.
You might not want to say it in public but it'll definitely work in your studying.
So, when the adrenal gland releases aldosterone.
That means the body hangs on to sodium, those kidneys will hang on to sodium
and you know the rule, wherever sodium goes what follows?
So, volume expansion comes from the release of aldosterone
that means the body hangs on to sodium and wherever sodium goes water follows.
Yeah, the vasoconstriction that comes from angiotensin II,
it is a very, very potent vasoconstrictor like four to eight times as active as norepinephrine.
Norepinephrine is a drug that we use usually in the critical care settings for someone
who is desperately life threateningly low blood pressure,
so this angiotensin II which my own body is capable of making with the RAAS
is four to eight times as potent as norepinephrine.
It's really impressive, that's why I told you, itâ's a bad mama jama.
So the RAAS, the end products of that end up with volume expansion and vasoconstriction.
Now, without looking at the screen what I want you to do is to think through this diagram,
see if you can look in the margin of your notes and recreate this diagram without looking at the notes.
Okay, now, let's pretend that we have unlimited resources and finances
and you and I are gonna solve the problem of treating hypertension.
Now, if you look at this process like a flow charts so let's say this is how the RAAS works, right,
we've got renin, angiotensinogen, angiotensin I, ACE and angiotensin II.
Okay, so, what kind of drugs could I design based on these steps,
how could I interrupt these steps or interfere with these steps
and so I don't make it all the way down to the action of angiotensin II?
Now, there is a point I want to point out,
angiotensin II, we know it is a really intense concept, right?
It's really amazing what it can do in the body,
but it doesn't really do anything unless angiotensin II has available angiotensin II receptors,
so before I get that -- all that reaction that we get,
you wanna make sure that the angiotensin II can actually make it to an angiotensin II receptor.
Now, that was a really big clue, if we were in an escape room together,
that would have been a really big clue but let's walk through it
because what would happen if we for say use direct renin inhibitors?
If we could make a drug that would inhibit renin, well, look at that if I have less renin
I'm gonna end up with less angiotensin II and I'm gonna end up with less angiotensin I, right,
because there won't be as much renin available to connect with the circulating angiotensinogen
therefore, I have less of every other product downstream.
Okay, cool! So if I have less renin,
I'm gonna end up with less potent vasoconstriction and volume expansion
because there's just gonna be less available so that would be cool,
if we could come up with a drug that would do that.
Now, what I if I could come up with a drug that just made less ACE available, less angiotensin converting enzyme?
Well, I'd still have lots of renin, angiotensinogen would be there and have angiotensin I but,
that's why I wouldn't have as much because if I have less ACE,
I have less things available to convert angiotensin I to angiotensin II, we know!
That means I would be able to lower my patient's blood pressure.
Okay, so we've talked about direct renin inhibitors and we've talked about ACE inhibitors,
so inhibitors let's talk about the blockers, okay!
So we've got a choice of angiotensin II receptor blockers or aldosterone receptor antagonist or blockers.
Okay, so if I could create a drug that was angiotensin II receptor blocker that means that that is a drug,
remember we've got unlimited resources and money,
that's a drug that is so uniquely created that it will slide right into an angiotensin II receptor
and once that drug is on there it blocks off that receptor.
So let's walk back through your flow chart.
If I've given my patient an angiotensin II receptor blocker, will I have renin?
Yes! Okay, well then, will I have circulating angiotensinogen?
Yes. Well then will I have angiotensin I? Yes.
But if I've given him an angiotensin II receptor blocker, will I have ACE? Yes!
So, will I end up with angiotensin II?
Yes, you will! But here's the deal, it would be all dressed up and no place to go because why?
Because you were smart enough to give your patient an angiotensin II receptor blocker.
Look at this receptor down here, it's all filled up.
So, when your body squirts out those substances and angiotensin II becomes available,
it can't connect to the receptor because you wisely gave you patient an angiotensin II receptor blocker,
so without that angiotensin II connecting to that receptor,
you're not gonna have the potent vasoconstriction or volume expansion.
Now, I've got another blocker up there.
You can see that we call it an antagonist, remember, we use those terms interchangeably,
antagonist and blocker, so our aldosterone receptor antagonist,
the same thing as our aldosterone receptor blocker.
So if I have a med that's an aldosterone receptor antagonist
that means that that medication is uniquely created that it will fit
and block the aldosterone receptors with the receptors not being available
because you gave the patient a medication, the body is not gonna know to hang on to sodium, right?
So you're not gonna have that, whatta, that follows, so your blood pressure will be lower.
So that's why understanding how the RAAS works
before we ever talked about the drugs really can help you understand their mechanism of action.
If we have less renin we definitely have less angiotensin II.
If we have less ACE, angiotensin converting enzyme, we're definitely gonna have less angiotensin II.
If we have an ARB, an angiotensin II receptor blocker, we're gonna have angiotensin II
but without its ability to connect to an angiotensin II receptor,
we're not gonna have that normal vasoconstriction or volume expansion.
If we try a patient on an aldosterone receptor blocker,
we're not gonna have the body hanging on to more sodium with water following for the volume expansion.
So understanding the RAAS is a really simple and straightforward way
to look at four groups or categories of antihypertensive medications.