Vasoactive Peptides

Question 1

Vasoactive peptides

Answer 1

polypeptide hormones, transmitters that have roles in ANS and CNS
-important effects on vascular and other smooth muscles, mediators of inflammation

Question 2

Vasoconstrictors

Answer 2

angiotensin II, vasopressin, endothelins, neuropeptide Y

Question 3

Vasodilators

Answer 3

bradykinin and other kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide

Question 4

Biosynthesis of angiotensin

Answer 4

• Angiotensinogen synthesized in liver as initial substrate and ciruclates in blood stream
• Renin secreted from kidneys, and cleaves angiotensinogen–> angiotensin I (removal of last 4 AA)
• Angiotensin I has little or no bio activity but circulates in blood stream
• Angiotensin I converted to Ang II by ACE (Angiogensin converting enzyme)

Question 5

Renin-angiotensin system

Answer 5

• driven by SNS
• long term regulation of CV fxn complementing short term NE release on peripheral vasculature
• primary mediator is ang II

Question 6

Renin secretion

Answer 6

• Renin synthesized and stored in juxtaglomerular apparatus of nephron in kidney
• Granular cells are site of synthesis, storage, and release of renin
• Location of macula densa beside renin secreting JG cells in afferent arteriole and regulates renin secretion

Question 7

Renin secretion inhibited by

Answer 7

1) inc NaCl flux thru chemoreceptors in macula densa
2) elevated BP thru baroreceptors in afferent arteriole wall
3) b-adrenergic blockade by inhibiting sympathetic stimulation via b1 adrenergic receptors
4) negative feedback by angiotensin II

Question 8

Actions of Ang II

Answer 8

• Inc peripheral resistance to inc afterload
• Stimulate aldosterone secretion to inc fluid volume and plasma volume and inc preload
• direct vasoconstrictor

Question 9

ACE inhibitors will act

Answer 9

oppositely to decrease both preload and afterload

-also protect against subsequent failure by slowing remodeling after MI

Question 10

ACE inhibitors

Answer 10

• pril
• all are prodrugs except for captopril
• all ACE inh are equally effective in blocking conv of Ang I to Ang II
• same clinical uses and same AE
• Inhibit converting enzyme that is happening mainly in lung
• Lower BP via reduced angiotensin vasoconstriction, dec aldosterone release which will dec blood volume and CO, red destruction of bradykinin (potent vasodilator, enhance BP lowering)

AE: cough and edema because inc bradykinin located in lungs and activation of sensory nerves in lung
-Also may increase renin release because diminishing neg feedback by ang II

Question 11

Toxicity of ACE inhibitors

Answer 11

-cough, angioedema, hyperkalemia due to inhibited aldosterone secretion esp in pts with renal insufficiency, teratogen

Question 12

Angiotensin Receptor Antagonist

Answer 12

Mainly selective for AT1

• may cause hyperkalemia esp in pts with renal insuf
• more specific in blocking ang effects because they do not affect bradykinin metabolism (no coughing or angioneurotic edema), but lose potential added benefit of circulating bradykinin levels
• losartan

Question 13

AT1r

Answer 13

Predominate in vascular smooth muscle in adults

Question 14

AT2r

Answer 14

occur mainly in fetal tissues

Question 15

Renin inhibitors

Answer 15

Aliskerin

• reduction in plasma renin activity and ang I and II and aldosterone concentrations
• red bp similar to those produced by ang II receptor antagonist

Question 16

Sympatholytic drugs will also inhibit

Answer 16

secretion of renin
-beta blocker will act to lower renin and ang levels as well- indirect modifier because there are beta receptors that lead to renin release when acted on by catecholamines

Question 17

Bradykinins and kalladin

Answer 17

• arteriodilators formed by enzymes called kallikreins and act on protein substrates called kininogens
• kinins released from pancreas, kidney, salivary glands, sweat
• inflammation effects promote redness, pain, swelling (leaky endothelium), heat
• produce pain

Question 18

kallikreins

Answer 18

present in plasma and many tissues

form kinins

Question 19

kininogens

Answer 19

present in plasma, lymph, interstitual fluid

acted on by kallikreins

Question 20

B1 kinin receptor

Answer 20

limited tissue distribution and fxn

Question 21

B2 kinin receptor

Answer 21

widely distributed and cause most biological effects

Question 22

b2 receptor antagonist

Answer 22

• icatibant

- used experimentally to evaluate kinin involvement in pain, hyperalgesia, inflammation; not available for clinical use

Question 23

b2 receptor agonist

Answer 23

may be useful for htn and CHF

Question 24

what contributes to antihtn effects of ACE inhibitors

Answer 24

bradykinin induced vasodilation- because ACE inh reduce bradykinin destruction and elevate plasma bradykinin levels

Question 25

Vasopressin

Answer 25

- Antidiuretic hormone (ADH) - Synthesized in hypothalamus w/ oxytocin and secreted or released from post pit - produces antiduiretic and vasopressor effects by acting on 3 receptors V1a, V1b, V2 - may constrict coronary blood vessels in pts with CAD

Question 26

V1a receptors

Answer 26

in VSM cause vasoconstriction and inc bp | -receptor antagonists

Question 27

V1b receptors

Answer 27

potentiate release of ACTH in pituitary

Question 28

V2 receptors

Answer 28

in renal cells produce antidiuresis by inc water permeability and reabsorption in collecting tubules

Question 29

desmopressin

Answer 29

- synthetic variant - mostly V2 receptor action - antidiuretic effect is more potent than vasoconstriction effect- more selective towards fluid retention side - used to tx diabetes insipidus

Question 30

Diabetes insipidus can be treated with

Answer 30

vasopressin and desmopressin

Question 31

conivaptan

Answer 31

v1a and v2 (vasopressin receptor) antagonist - used to treat hyponatremia -will lead to sodium retention

Question 32

endothelins

Answer 32

potent vasoconstrictor substances -locally acting -et1, et2, et3 direct positive inotropy and chronotropy -rapid and transient BP decrease but prolonged inc in BP -Contract bronchial smooth muscle -Dec glomerular filtration and sodium, water excretion -inc secretion of renin, aldosterone, vasopressin, anp

Question 33

ETA receptor

Answer 33

endothelin a receptor | -on smooth muscles, promotes vasoconstriction

Question 34

ETB receptor

Answer 34

endothelial release of EDRF (endothelium derived relaxation factor- NO) and prostanoids (similar to muscarinic effect or histamine)

Question 35

Bosentan

Answer 35

- nonselective ETA/ETB receptor antagonist - approved for pulmonary htn - AE: systemic hypotension, hepatotoxicity

Question 36

Phosphoramidon

Answer 36

endothelin converting enzyme inhibitor | -non specific for endothelin converting enzyme

Question 37

Substance P

Answer 37

- 11 amino acid tachykinin peptide - Rapidly acting vasodilator - contracts intestinal, bronchiolar smooth muscle - Stimulates glandular secretion - NT in CNS and enteric NS - inflammatory mediator in periphery - Makes endothelium leaky

Question 38

Other tachykinins

Answer 38

Neurokinin A, neurokinin B

Question 39

three G protein coupled neurokinin receptors are

Answer 39

NK1, NK2, NK3

Question 40

Nonpeptide NK1 receptor antagonists

Answer 40

- developed as potential analgesics, under trial as antidepressants - prevents chemotherapy induced emesis

Question 41

CGRP

Answer 41

Calcitonin gene related peptide - distributed widely in CNS and PNS - most potent vasodilator yet discovered - release of CGRP from trigeminal nerves may produce migraine - 2 receptors: CGRP1 and CGRP2

Question 42

Neuropeptide Y

Answer 42

- one of the most abundant neuropeptides in CNS and PNS | - frequently colocalized in noradrenergic neurons in NE

Question 43

Effects of neuropeptide Y in CNS

Answer 43

increased feeding, hypotension, hypothermia, and resp depression

Question 44

Effects of neuropeptide Y in PeripheralNS

Answer 44

Vasoconstriction of cerebral blood vessel, positive inotropic and chronotropic actions, hypertension -When released NE will provide slow, long lasting vasoconstriction

Question 45

Neuropeptide Y receptors

Answer 45

Y1- cardiovascular and peripheral effects | Y5- CNS control of food intake

Question 46

Vasopeptidase inhibitors

Answer 46

Many vasoactive peptides are inactivated by endopeptidases - vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase- increase levels of natriuretic peptides and decrease formation of angiotensin II - enhance vasodilation, reduce vasoconstriction, increase sodium excretion - decrease peripheral vascular resistance and blood pressure - produce angioedema and cough (because they inhibit ACE)

Question 47

ACE inhibitor list

Answer 47

-prils | benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril

Question 48

Ang receptor antagonist

Answer 48

-sartans | candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan

Question 49

Neurokinin-1 receptor antagonist

Answer 49

Aprepitant