Vasoactive Peptides and Inhibitors: RAAS

Question 1

Where is renin produced and what is unique about this enzyme in the RAAS system?

Answer 1

-Kidney -rate limiting step in RAAS pathway and therefore can be a big drug target

Question 2

Overview of RAAS enzymes and what they substrates

Answer 2

1. renin released from kidney turns angiotensinogen into angiotensin I 2. ACE turns AG1 into AG2

Question 3

4 triggers of renin release from the kidney

Answer 3

hypovolemia hyponatremia hypohypotension adrenergic activation

Question 4

5 organs Angiotensin II affects

Answer 4

1. brain: drink water, eat salt, central pressor (SNS stim.), ADH release, ACTH release, oxytocin release 2. kidney: inhibits renin release, Na and water retention 3. adrenal cortex: aldosterone secretion 4. gut: fluid absorption 5. vasc. smooth muscle: pressor

Question 5

RAAS system negative feedback

Answer 5

1. AG2 turns off renin conversion to form AG1 2. Receptor occupancy: optimal receptor occupancy by AT1= reduces AG1 formation

Question 6

Most potent vasoconstrictor made in vivo

Answer 6

Angiotensin II

Question 7

Homeostatic role of AGII in normal condition

Answer 7

-when SAP drops, renin release is increased. In addition to an increase in SNS which further increases renin release. but the renin increases AG2 which vasoconstricts, and releases aldosterone which increases intravascular volume.VasoC and increase Na retention help to restore BP

Question 8

Major angiotensin II receptor subtypes

Answer 8

AT1: highest distribution of receptors in vascular smooth muscle, kidney, adrenal cortex, CNS, pituitary…this is the major player for us!! remember this one!

AT2: highest distribution in uterus, fetus; can be induced in other tissues by unknown mechanisms

both are GPCRs

Question 9

Response of AGII binding to AT1 vs AT2

Answer 9

AT1: vasoconstriction, aldosterone release, cell proliferation/hypertrophy/matrix deposition; THIS IS THE BAD GUY RECEPTOR!

AT2: vasodilation, bradykinin/NO/cGMP release, antiproliferation, apoptosis

Question 10

Which AGII receptor is blocked by all available angiotensin receptor antagonists?

Answer 10

AT1: remember this is the receptor responsible for vasoconstriction, aldosterone release, cell proliferation/hypertrophy/matrix deposition!!

Question 11

T/F: AT1 receptor really only transduces signals involved in messing up the CV system.

Answer 11

False; part of many complex signaling pathways

Question 12

Angiotensin II effects on CNS

Answer 12

can gain access to brain regions lacking BBB and may also be produced within the brain

responses include: central pressure from activating SNS, endocrine release of ADH, ACTH, behavioral increase in thirst and Na appetite

Question 13

RAAS effects on the sympathetic nervous system

Answer 13

increases release and decrease uptake of NE from postganglion neurons

enhances sensitivity of target tissues to NE

net effect= vasoconstriction

Question 14

RAAS effect on the adrenal medulla

Answer 14

release of catecholamines from chromaffin cells

Question 15

RAAS system effects on adrenal cortex

Answer 15

stimulates synthesis and release of aldosterone from zona glomerulosa cells

action is augmented by hyponatremia and hyperkalemia

Question 16

RAAS effects on the kidney

Answer 16

antidiuresis and antinatriuresis

reduces GFR

inhibits renin release as a function of negative feedback

Question 17

Actions and implication of angiotensin II on CVD

Answer 17

1. vasoconstriction= HTN
2. GF-like effects on cardiac myocytes and SMCs= cell proliferation/apoptosis, hypertrophy–precipitating factors to LV dysfunction
3. pro-inflammatory response in vascular tissue= impairs endothelial function and induces oxidation

Question 18

Give an example for class of the effects of angiotensin II and endothelial dysfunction via oxidation

Answer 18

1. AGII leads to activation of NAD(P)H oxidase and formation of ROS
2. this leads to oxidation of LDL and LDL-receptors which increase endothelial uptake of LDL
3. leads to damage due to lipid accumulation within cells adn also the formation of plaques in athersclerosis
4. also initiated inflammation in VSMCs and endothelial cells via NFkB activation

Question 19

Describe the vicious cycle of AGII and atherosclerosis

Answer 19

AG2 begins to cause oxidative stress, LDL uptake, injury, cytokines, and inflammation. Immune cells coming to the area release other enzymes that can create AG2 and further this process

Question 20

Summarize the effects of AG2 causing increase peripheral resistance (4 ways)

Answer 20

1. direct vasoconstriction
2. enhancement of PNS: increase NE release, decrease NE reuptake, increase vascular sensitivity to NE
3. increase sympathetic disease (CNS)
4. release of catecholamines from adrenal medulla

all of these = rapid pressor response

Question 21

3 main ways AGII leads to decreased renal function

Answer 21

1. direct effect to increase Na reabsorption in prox tubule
2. release of aldosterone (increase Na reabsorption and K excretion in distal tubule)
3. Alteral renal hemodynamics: direct renal vasoconstriction, enhaved NE transmission in kidney, increase renal sympathetic tone (CNS)

Question 22

Hemodynamic and non-hemodynamic ways AG2 leads to vascular and cardiac hypertrophy and remodeling

Answer 22

1. non hemo ways: increase expression of proto-oncogenes, increased production of GFs, increase synthesis of ECM
2. hemo ways: increased afterload (cardiac) and increased wall tension (vascular)

Question 23

5 drug classes that can alter the RAAS system

Answer 23

1. B-blockers: block adreneric activation and renin release
2. renin inhibitors (DRIs)
3. ACE inhibitors
4. Angiotensin II Receptor Blockers (ARBs)
5. Mineralocortoid R antagonists

Question 24

List 4 ACE inhibitors

Answer 24

1. Captopril
2. Enalapril
3. Lisinopril
4. Ramipril

Question 25

Effect of ACE-Is on feedback loop

Answer 25

-because they decrease levels of AG2, this will cause increased levels of renin by relieving suppression of its release and by decreased AT1 receptor occupancy

Question 26

3 potential limitations with ACE inhibition

Answer 26

1. Alternate pathways for AGII production: bypass pathways leading to ACE escape where chronic administration of ACEIs fails to consistently suppress AngII levels
2. Non-specificity of the enzyme: reason why ACE espace was still experiencing low BP; inhibiting ACE increased bradykinin/NO to generate vasodilation
3. Poor side effect profile: increase bradykinin= cough, angioedema, renal dysfunction, hypotension; also antigrowth and antiproliferative

Question 28

Pros and Cons to using ARBs

Answer 28

• do not inhibit the destruction of bradykinin, and therefore, do not cause cough, renal dysfunction, and angioedema
• on the other hand, they lack some of the potentially beneficial vasodilatory effectors of bradykinin. Thought that perhaps if AT1 is blocked, AT2 may not bind AngII and cause vasodilation this way.

Question 29

Effect of ARBs on negative feedback loop of RAAS

Answer 29

-ARB will block receptor occupancy of AT1 which will limit negative feedback, but AngII levels will still be high and can make up for this by blocking renin release.

Question 30

Bypass pathways exist to create AngII in the presence of ACEIs. Are these bypass pathways more or less active in dysfunctional vessels?

Answer 30

more function: increasingly unhealthy vessel were found to have greater levels of bypass pathway enzymes. This accounted for their consistent levels of AngII after prolonged ACEI.

Question 31

Impact of RAAS suppression by ACEIs and ARBs beyond blood pressure control.

Answer 31

-both agents when used alone improve renal and CV outcomes which decrease mortality

Question 32

Utility of direct renin inhibitors as being complementary to ACEIs and ARBs

Answer 32

-these pathways weaken the negative feedback loop and thus, renin is not suppressed. Blocking renin directly can offer release of this.

Question 33

Effects of diuretics, ACEIs, ARBs, and renin inhibitors on PRA (plasma renin activity), AngI and Ang II

Answer 33

-note that DRI bind renin (so PRC is increased) but its not active so PRA is reduced.

Question 34

Summary of sites of actions of drugs that interfere with RAAS (4 drug classes)

Answer 34