Vasoactive Peptides: RAAS

Question 0

5 organs/tissues that angiotensin II (A-II) affects? (Effects on each?)

Answer 0

Brain (Na+ appetite, thirst, ADH, ACTH, etc.)
Kidney (neg feedback, Na+ retention)
Adrenal (aldosterone release)
Gut (more fluid absorption)
Vascular smooth muscle (pressor response)

Question 1

4 triggers for renin release?

Answer 1

Hypovolemia
Hyponatremia
Hypotension
Adrenergic Activation

Question 2

What are the receptors for A-II?

Where are they predominantly expressed?

Answer 2

AT1 subtype- kidneys, adrenal, pituitary, cortex, vascular smooth muscle
AT2 subtype- uterus and fetus (inducible in others)

Question 3

What effects does AT1 receptor binding produce?

Answer 3

The things you normally associate with A-II:

Vasoconstriction, aldosterone release, cell proliferation, hypertrophy, and matrix deposition.

Question 4

What effects does AT2 binding produce?

Answer 4

Vasodilation (bradykinin, NO, cGMP), antiproliferation, and apoptosis.
-opposite from what you usually expect from A-II… but these effects certainly don’t predominate.

Question 5

What does A-II cause when in crosses the BBB?

Answer 5

Central pressor response via sympathetics.
Increased thirst / Na+ appetite.
Release of ACTH and ADH.

Question 6

Endo review: Which part of the adrenal cortex releases aldosterone?

Answer 6

The zona glomerulosa.

interesting that A-II acts both directly on the ZG this way and indirectly by inducing ACTH release

Question 7

Effects of A-II on the kidney?

Answer 7

Decreases natriuresis and diuresis.
Reduces GFR.
Inhibits renin release (negative feedback).

Question 8

Does A-II induce a pro-inflammatory response in vascular tissue?

Answer 8

Yep, accelerating atherosclerosis.

So, it does everything bad for your circulation (unless you’ve been bitten by a tiger and you’re bleeding out).

Question 9

What’s the relevance of the Lox-1 receptor to A-II activity?

Answer 9

A-II upregulates Lox-1 on endothelial cells.

Lox-1 facilitates uptake of oxidized LDL into endothelial cells -> endothelial damage.

Question 10

How would you inhibit the sympathetic stimulation of renin release?

Answer 10

beta blockers

Question 11

What’s the rate limiting step in A-II production? Can you inhibit this?

Answer 11

Renin release.

There are renin inhibitors…. but they’re not really used.

Question 12

What’s the mainstay of targeting the RAAS?

Answer 12

ACE inhibitors

Question 13

What are 3 limitations to ACE inhibition?

Answer 13

There are other enzymes make A-II. (and they’re upregulated after ACEi use)
ACE has other functions. (though, this is also a good thing)
Poor side effect profile.

Question 14

How do A-II levels change with long-term ACEi use? How does this correlate with reduction in BP / other desirable things?

Answer 14

A-II levels initially drop significantly, but then rebound to about the same levels.
Actually, the BP reductions persist despite the rebound in A-II. This is mostly mysterious, though bradykinin may play a role.

Question 15

What is another vasoactive peptide that ACE converts?

Answer 15

ACE deactivates bradykinin by cleaving it into inactive fragments.

Question 16

3-4 positive effects of bradykinin?

Answer 16

Reduced BP
NO production (via eNOs)
Anti-growth
Anti-proliferation

Question 17

3 negative effects of bradykinin?

Answer 17

Cough
Angioedema
Renal dysfunction

Question 18

Pros and cons of angiotensin receptor blockers (ARBS)?

Answer 18

Basically they have to do with bradykinin.
Pros: no cough or angioedema from increased bradykinin.
Cons: you don’t get the vasodilation and anti-proliferative effects of bradykinin.

Question 19

What are 2 ways negative feedback for A-II happens?

Answer 19

High A-II levels.
A-II binding its receptor.
(it’s a little confusing why these are distinct.. but…)

Question 20

How does A-II rev up sympathetic signaling?

Answer 20

Increases NE release, decreases NE reuptake -> more NE in synapses.
Promotes catecholamine release from chromaffin cells.