Renin Angiotensin System, Vasopressin and Kinins

Question 1

What are the 3 components of the circumventricular organs?

Answer 1

Area postrema
Subfornical organ
Organum vasculosum of the lamina terminalis

Question 2

Broadly speaking, the MAS receptor is cardio [protective/damaging]. Its ligand is _. The AT2R and AT1R receptors are cardio [protective/damaging], their ligands are _

Answer 2

MAS - protective - Ang1-7
AT2R- Damaging - Ang II
AT1R - Damaging - Ang III/ II

Question 3

Ang I is biologically [active/inactive]. It is converted to Ang II and Ang III by _.

Answer 3

• inactive

- ACE and aminopeptidases

Question 4

What is the ACE-AngII-AT1 signalling axis known for?

Answer 4

Hypertension, stroke and cardiovascular disease

Question 5

What is the product of ACE2 and endopeptidases? What is the precursor?

Answer 5

Ang 1-7

Ang I and Ang II

Question 6

What is the ACE2-Ang 1-7 -MAS signalling axis known for?

Answer 6

Cardioprotective branch of the RAS pathway

Question 7

What is the source of renin? What is its function?

Answer 7

Kidney

Angiotensinogen to angiotensin

Question 8

What are 3 mechanisms that increase renin release?

Answer 8

Decreased afferent arteriole stretch (kidney)
Reduced sodium sensed by macula densa
Increased renal nerve activity

Question 9

What are 3 molecules that feed back to inhibit renin release?

Answer 9

Ang II
Vasopressin (AVP)
Potassium

Question 10

Feed back inhibition from Ang II is lost when what 2 classes of drugs are used?

Answer 10

ACE inhibitors

AT1 receptor blockers

Question 11

What is the effect of decreased arterial pressure on renin release? What are the two mechanisms enacted?

Answer 11

Increased release
Direct mechanism - renal baroreceptors
Indirect mechanism - systemic baroreceptors /baroreflex

Question 12

What is the effect of dehydration/ hemorrhage on renin release?

Answer 12

Increased release

Question 13

What is the effect of hyponatremia on renin release? What senses this?

Answer 13

Increased renin release

The macula densa

Question 14

What are 4 mechanisms by which Ang II and Ang III raise arterial pressure?

Answer 14

• Direct vasoconstriction (AT1R on smooth muscle)
• CNS - Increased vasopressin and SNS release
• Peripheral NS - increased norepinephrine
• Adrenal medulla - Increased epinephrine release

Question 15

True or false: Ang II and Ang III are able to cause increase HR and tissue hypotrophy?

Answer 15

False, bith cause increased HR and HYPERtrophy

Question 16

What is the effect of angiotensin on thirst and vasopressin release? What is stimulated to increase thirst?

Answer 16

Increases both

Circumventricular organ

Question 17

What are the effect of angiotensin on the adrenal medulla?

Answer 17

Stimulates the release and synthesis of aldosterone

Question 18

What are the 2 mechanism by which the RAS can be detrimental during heart failure?

Answer 18

Increased renin (reduced renal blood flow) leads to

• increased peripheral resistance (increased afterload)
• Increased water retention (increased preload)

Question 19

Which of Ang II, Ang III and Ang 1-7 promotes

• hypertrophy, tissue remodeling and organ damage
• counteracts vascular remodeling/hypertrophy and organ damage

Answer 19

• Ang II and Ang IIi first bullet

- Ang 1-7 second bullet (via MAS receptor)

Question 20

What are 2 mechanism by which the RAS increases sodium retention?

Answer 20

• vasoconstriction (less into glomerulus)

- increased reabsorption from proximal tubule

Question 21

True or false: Angiotensin receptors are ion channels

Answer 21

False, the angiotensin receptors are GPCRs

Question 22

What is the second messenger for AT1R? What is the effect of its activation?

Answer 22

Phospholipase C, Calcium and MAPK

Vasoconstriction

Question 23

What is the second messenger of AT2R? What is the effect of its activationb (2)

Answer 23

Nitric oxide, also block MAPK

Vasodilation

Question 24

AT1 and AT2 receptors have opposing actions on blood vessels. What are they? Which dominates? Why?

Answer 24

AT1 - vasoconstriction
AT2 - vasodilation
AT1 dominates because more of the receptor is present in the blood vessel

Question 25

What is the effect of MAS receptor activation? (3) What are the 2 second messengers?

Answer 25

Vasodilation Antiinflammation Anti cell proliferation NO and Calcium

Question 26

What are the 4 examples of AT1 receptor antagonists provided? What condition would they be used for? When would a patient be considered for an AT1 receptor blocker?

Answer 26

Losartan, valsartan, candesartan and irbesartan Heart failure If a patient doesn't respond to ACE inhibitors

Question 27

How have the blood pressure lowering effects of AT1 receptor blockers been explained?

Answer 27

The residual effects of the AT2 receptor vasodilation and naturesis (no longer counteracted by AT1 mediated vasoconstriction and sodium retention)

Question 28

How can feedback contribute to the blood pressure lowering effects of AT1 receptor blockers?

Answer 28

AT1 block = no feedback, increased renin release from kidney, more Angiotensin (and all its metabolites) production, including Ang 1-7 and ACE2

Question 29

What are 3 major side effect of angiotensin receptor blockers?

Answer 29

Hypotension Hyperkalemia Acute renal failure (in renal insufficiency patients)

Question 30

What are 2 populations where angiotension receptor blockers are contraindicated?

Answer 30

Pregnant women | Nursing mothers

Question 31

What are the 6 examples of ACE inhibitors provided?

Answer 31

``` Captopril Enalapril Lisinopril Ramipril Quinapril Fosinopril ```

Question 32

What are 4 uses of ACE inhibitors?

Answer 32

Hypertension (Major use, major agent) Left ventricular systolic dysfunction Myocardial infarction Heart failure

Question 33

In addition to the side effects of AT1 receptor blockers, what are 2 additional side effects of ACE inhibitors? What is the mediating molecule?

Answer 33

Dry cough Angioedema Bradykinin is mediator of angioedema

Question 34

How may Ang 1-7 play a role in the blood pressure lowering effects of ACE inhibitors?

Answer 34

ACE degrades Ang 1-7 | ACE also degrades Ang I, a precursor for Ang 1-7

Question 35

What is the example of the renin inhibitor available for the treatment of hypertension? What are its side effects?

Answer 35

Aliskiren | Same as ACE inhibs + AT1R inhibs AND GI/allergic symptoms

Question 36

In addition to the kidney, what are 2 additional areas where renin is made?

Answer 36

Vascular smooth muscle | Brain

Question 37

What are kinins? What 2 enzyme families make kinins?

Answer 37

Vasodialator peptides | Kininogens and kallikreins

Question 38

What is the predominant kinin in the blood? What is its effect on arterioles? Large arteries? Large veins?

Answer 38

Bradykinin Dilates arterioles Constricts large arteries and most veins

Question 39

What is the effect of kinins infused into normotensive subjects? What is the effect of kinin antagonists in these same subjects? What is the conclusion

Answer 39

Vasodilation No effect in normotensive subjects - bradykinin is probably important in modulating Pa in hypertensive situations but it does not contribute to maintenance of basal Pa in normotensive subjects

Question 40

What is the effect of kinins on capillary permeability? On the sympathetic ganglia?

Answer 40

Increases capillary permeability | Minor - stimulate sympathetic ganglia, also increase epinephrine release

Question 41

In addition to its cardiovascular role, kinins also play a role in what 3 other processes?

Answer 41

Glandular secretion Inflammation (edema) Pain

Question 42

What type of receptors are the kinin receptor? What is the major physiological agonist? What are the 2 end products of the second messenger system that mediate their effects?

Answer 42

GPCRs Bradykinin Nitric oxide and prostaglandins

Question 43

The major agonist for the B1 subtype of the kinin receptor is _. It has what effect on vascular smooth muscle?

Answer 43

des-Arg-bradykinin | contraction of vascular smooth muscle

Question 44

How does Kininase II link the kinin and angiotensin signalling systems? What drug family inhibits kininase II?

Answer 44

Kininase II inactivates bradykinin. It is the same enzyme that converts Ang I to Ang II. ACE inhibitors

Question 45

What is another name for vasopressin? What is its major function? Mutations in the protein or receptor can lead to what disease?

Answer 45

Antidiuretic hormone Regulation of body osmolality Diabetes insipidus

Question 46

What are 3 major conditions that can increase the release of vasopressin (ADH)?

Answer 46

Decreased arterial pressure Decreased fluid volume / increased plasma osmolality pain/nausea/hypoxia/hormones

Question 47

In addition to its antidiuretic actions, what is a direct and an indirect action of vasopressin?

Answer 47

Direct - vasoconstriction | Indirect - Bradycardia

Question 48

What are the 2 receptor subtypes for vasopressin? What are their associated g-proteins? What actions do they mediate?

Answer 48

V1 - Gq - cardiovascular effects | V2 - Gs - Antidiuretic effects

Question 49

A mutation in which of the vasopressin receptors can cause diabetes insipidus?

Answer 49

V2

Question 50

What are the 2 examples of vasopressin antagonists discussed? What is their receptor specificity?

Answer 50

Conivaptan - V1/V2 | Tolvaptan - V2 selective

Question 51

How do the target diseases for conivaptan and tolvaptan differ?

Answer 51

Conivaptan - hyponatremia from SIADH | Tolvaptan - hyponatremia from fluid retention resistant to fluid restriction (CHF, SIADH, cirrhosis)

Question 52

Vasopressin can be pathological in hypertension. It can also be pathological in heart failure. How can antagonists be used to tackle aspects of heart failure mediated by vasopressin?

Answer 52

V1 antagonists - reduce afterload | V2 antagonists - treat hyponatremia