Pbd Final Exam Ras

Front 1

Major effects of the RAS system

Back 1

Maintain BP, salt & water balance

Front 2

Minor effects of the RAS system

Back 2

Vasoconstriction
Role in inflammation

Front 3

RAS is composed of a ________ and a _________ system

Back 3

Systemic (vascular)
Local (tissue)

Front 4

RAS is involved in long-term or short-term regulation of BP?

Back 4

Both - long term and short term

Front 5

Precursor protein for the family of angiotensin peptides (the RAS)

Back 5

Angiotensinogen

Front 6

Earlier names for angiotensinogen protein (2)

Back 6

Angiotonin
Hypertensin

Front 7

Main function of angiotensinogen:

Back 7

It is the rate-limiting factor in the activity of the systemic renin angiotensin system

Front 8

Angiotensinogein is primarily synthesized in what type of cells?

Back 8

Hepatocytes

Front 9

Other sites of synthesis for angiotensinogen (not the primary site):

Back 9

CNS, heart, vasculature, kidney, adipocytes

Front 10

Is angiotensinogen stored in the body?

Back 10

No, it is constantly made and secreted.

Front 11

What is the form of angiotensinogen in circulation?

Back 11

Pre-pro-angiotensinogen

Front 12

How do adipose tissue and estrogen from hepatocytes regulate the production of angiotensinogen?

Back 12

Upregulate production by upregulating the mRNA.

Front 13

Angiotensinogen is transcriptionally controlled via specific regulatory DNA sequences of its gene by which substances?

Back 13

Glucocorticoids, estrogen, thyroid hormone, insulin, some cytokines

Front 14

Glucocorticoids, estrogen, thyroid hormone, insulin, and select cytokines have what affect on angiotensinogen?

Back 14

Control its release from producing cells by affecting the angiotensinogen gene on a transcriptional level

Front 15

What enzyme cleaves angiotensinogen, where does the cleavage occur, and what product results?

Back 15

Cleaved by renin;
Cleaved in circulation;
Produces Ang I, an N-terminal decapeptide

Front 16

What effect does Ang II have on release of angiotensinogen?

Back 16

Angiotensinogen synthesis can be stimulated by Ang II

Front 17

What effect does inflammation have on release of angiotensinogen?

Back 17

Release is stimulated by inflammation

Front 18

By what mechanism does Ang II exert positive feedback regulation on the release of angiotensinogen?

Back 18

Via an AT1 (Angiotensin 1) receptor

Front 19

What is the genetic evidence that suggests that angiotensinogen contributes to the hypertensive phenotype?

Back 19

Knockout studies in animals;
Polymorphisms within the angiotensinogen gene have been genetically linked with familial HTN

Front 20

A highly substrate- and species-specific aspartyl protease enzyme

Back 20

Renin

Front 21

What enzyme catalyzes the rate limiting step in the RAS system?

Back 21

Renin

Front 22

Name the three molecules of the RAS cascade and the two enzymes that catalyze their transformations

Back 22

Angiotensinogen --> Angiotensin I (catalyzed by Renin);
Angiotensin II --> Angiotensin II (catalyzed by ACE)

Front 23

What cells are the systemic source for renin synthesis, storage, and release? Where are they located?

Back 23

Juxtaglomerular cells; located in the afferent arteriole

Front 24

What is the first step in the synthesis of renin?

Back 24

The formation of pro-pre-renin

Front 25

What enzyme mediates the cleavage & activation of renin from pro-pre-renin?

Back 25

Cathepsin B

Front 26

How is renin stored and how is it released?

Back 26

It is stored in granules in the juxtaglomerular cells and released through exocytosis into the vascular lumen

Front 27

The secretion of renin from the juxtaglomerular cells is regulated primarily by what three pathways?

Back 27

1. Macula densa pathway (kidney)
2. Intrarenal baroreceptor pathway (kidney)
3. Beta-adrenergic receptor pathway (nervous system)

Front 28

What is the macula densa and where in the kidney is it located?

Back 28

It is a modified plaque of cells, located in the distal tubule of the nephron, at the end of the loop of Henle and adjacent to the afferent arteriole and the juxtaglomerular cells

Front 29

What substance is sensed/monitored by the macula densa? What does a change in this substance initiate?

Back 29

Sodium levels. Decreased Na+ levels initiate a cascade of events that ultimately stimulates renin release

Front 30

PGE2 and Cox 2 inhibit or stimulate renin release?

Back 30

Stimulate

Front 31

Adenosine inhibits or stimulates renin release?

Back 31

Inhibits

Front 32

What is the most powerful regulator of renin release?

Back 32

BP, via the intrarenal baroreceptor pathway

Front 33

The renal baroreceptor inhibits or stimulates renin release in response to reduced renal perfusion pressure?

Back 33

Stimulates

Front 34

The juxtaglomerular cells are directly innervated via the sympathetic nerves. Direct stimulation of these nerves will increase or decrease renin release?

Back 34

Increase

Front 35

Ang II inhibits or stimulates renin release?

Back 35

Inhibits

Front 36

By what two pathways does Ang II regulate renin release? Hint: one is a short-loop negative feedback system and one is a long-loop negative feedback system

Back 36

Ang II stimulates AT1R...
Short-loop: on the JC cells to inhibit renin release
Long-loop: to increase BP, which inhibits renin release

Front 37

cAMP (stimulates/inhibits) renin release and cGMP (stimulates/inhibits) renin release

Back 37

cAMP: stimulates
cGMP: inhibits

Front 38

An increase in intracellular calcium (stimulates/inhibits) renin release

Back 38

Inhibits
Increasing cytosolic Ca++ leads to a decrease in cAMP.

Front 39

An enzyme found in plasma, but that is membrane-bound to endothelial & epithelial cells

Back 39

ACE (angiotensin converting enzyme)

Front 40

What is the preferred substrate of ACE, and what effect does ACE have on it?

Back 40

Bradykinins - ACE inactivates.

Front 41

An alternative pathway to ACE that converts Ang I to Ang II

Back 41

Chymase enzyme

Front 42

Where is ACE predominantly found?

Back 42

On endothelial cells in the lung, retina, and brain; on epithelial cells in the kidney and gut

Front 43

What is the function of the ACE 2 enzyme?

Back 43

Catalyzes the formation of Ang 1-7, a vasodilator molecule, from both Ang I and Ang II

Front 44

Is ACE 2 susceptible to ACE inhibitors?

Back 44

No.

Front 45

What are the two specific receptors for Ang II and which is most common?

Back 45

AT1R and AT2R; AT1R is most common, AT2R is widely distributed in fetal (developmental) tissues

Front 46

What are the functions of the AT2 receptors?

Back 46

Oppose actions of Ang II on AT1 receptors: vasodilate, anti-proliferative

Front 47

How do ACE inhibitors protect the CV system?

Back 47

They block degradation of Ang 1-7, which can inhibit Ang II actions, to vasodilate; they increase bradykinin, which also vasodilates; they increase ACE 2 levels and subsequently increase Ang 1-7 levels.

Front 48

Ang II is not only produced via the endocrine RAS, but is also produced via ____________ in local systems

Back 48

Paracrine/autocrine

Front 49

What actions can locally-formed angiotensins have (as opposed to systemically formed)

Back 49

Growth factors, neurotransmitters, smooth muscle constrictors.

Front 50

What are two local systems where the RAS is found and what specific function might they have there?

Back 50

Skin - may be involved in wound healing since Ang II levels are increased after injury
Pancreas - strong association with high levels of ACE and pancreatic disfunction with obesity, HTN, and diabetes

Front 51

What are the major roles of Ang II?

Back 51

Regulation of BP and salt & volume homeostasis

Front 52

What effect does Ang II have on TPR?

Back 52

Increases, via direct & indirect effects

Front 53

How does Ang II affect cardiovascular STRUCTURE?

Back 53

Stimulates hypertrophy of VSM:
a. Hemodynamically by increasing pressure
b. Nonhemodynamically by stimulating growth factors
Remodeling: collagen formation
Vasoconstriction of VSM
Mitogenesis of VSM

Front 54

RAS contribution to disease states other than CV

Back 54

Atherosclerosis: oxidative stress & pro-inflammatory effects
Generation of reactive oxygen species: increase in free radicals leads to endothelial dysfunction
Pro-thrombotic effects: stimulation of plasminogen activator inhibitor (PAI breaks down plasmin, plasmin breaks down clots)

Front 55

How might the RAS effects on thrombotic events correlate to its overall function?

Back 55

RAS controls BP. Hemorrhage affects BP. Clotting stops bleeding and helps maintain BP when hemorrhaging, but when there is no hemorrhagic event, the RAS inhibition of dissolving clots is a problem.

Front 56

Ang II may act as a _________, which relates to its pro-inflammation effects as a growth promotor and a pro-inflammatory modulator

Back 56

Cytokine

Front 57

One of the pro-inflammatory effects of Ang II is that is can recruit cells. Which type of cells responds to Ang II?

Back 57

Monocytes.

Front 58

Ang II, along with potassium, regulates the secretion of what steroid?

Back 58

Aldosterone

Front 59

Where is aldosterone produced and where in the body?

Back 59

In the zona glomerulosa of the adrenal cortex

Front 60

What type of steroid is aldosterone?

Back 60

Mineralocorticoid

Front 61

What is the major function of aldosterone?

Back 61

To act on renal & other epithelia to enhance sodium reabsorption & increase the excretion of potassium & hydrogen ions

Front 62

What are some trtmts for HTN that involve the RAS?

Back 62

Renin inhibitors
ACE inhibitors
AT1R antagonists
ACE2/AT2R/Ang 1-7 agonists

Front 63

Why are ACE inhibitors and ARB (AT1R antagonists) contraindicated in pregnant women?

Back 63

They can affect developmental of fetal organs, including the kidney

Front 64

In the HOPE study, ACE inhibitors were shown to reduce MIs in pts with CV disease. What were the effects of ACE I on:
Cardiac hypertrophy:
Ang II:
Plasmin levels:
Platelets:
Bradykinin:
Ang 1-7:
ACE 2:
Blood pressure:

Back 64

Reduce cardiac hypertrophy
Decrease Ang II (& hence PAI-1, which increases plasmin levels & breaks down clots)
Reduce platelet action
Increase bradykinin levels
Increase levels of Ang 1-7 & ACE2
Reduce BP & hence decrease load on heart

Front 65

The discovery of what receptors in 2007 is leading to a new class of antihypertensive agents?

Back 65

The prorenin receptor

Front 66

What is the new renin inhibitor for the prorenin receptor?

Back 66

Aliskiren

Front 67

T/F: Aliskiren binds only prorenin on tissues

Back 67

False. It binds renin and prorenin, but the ratio of renin to prorenin is 1:7 in normal individuals

Front 68

What effect does an overexpression of prorenin receptors have in transgenic mice?

Back 68

Increased BP

Front 69

What series of intracellular events is triggered by the activation of the prorenin receptors?

Back 69

1. Activation of PAI-1
2. Activation of fibrotic extracellular components such as fibronectin & collagen
3. Increases levels of TGF-beta

Front 70

What does the effect of the activation of prorenin receptors on levels of TGF-beta suggest?

Back 70

Increased levels of TGF-beta suggest that renin may contribute to hypertrophy & fibrosis, independent of Ang II action or generation

Front 71

What angiotensin peptide has been discovered in 2008, that is another angiotensin precursor?

Back 71

Angiotensin 1-12