NO, ET and AII

Question 1

how is vascular smooth muscle tone controlled?

Answer 1

controlled by mediators that increase/decrease tone, such as those secreted from:

sympathetic nerves (noradrenaline)

vascular endothelium (nitric oxide NO, ET-1)

circulating hormones (adrenaline, Angiotensin II (ATII))

Question 2

How is nitric oxide (NO) synthesized?

Answer 2

NO is synthesized from l-arginine and molecular oxygen (O2) by nitric oxide synthase (NOS).

Question 3

How many isoforms of nitric oxide synthase (NOS) exist? what are they?

Answer 3

3 forms of NOS. named according to activity/tissue type in which they were first described.

Neuronal NOS (nNOS) associated with neurons. constitutive, present in CNS and autonomic nerves.

Endothelial NOS (eNOS) associated with endothelium. constitutive, present in endothelial cells and platelets.

inducible NOS (iNOS) inducible, can be produced in response to various stimuli. induced in macrophages and other cells by interferon-(gamma)

Question 4

how is cyclic GMP synthesized?

Answer 4

NO activates guanylyl cyclase, which synthesizes cyclic GMP.

Question 5

what is cyclic GMP (cGMP) and what does it do? what inactivates it?

Answer 5

a second messenger, activate protein kinase G.
phosphodiesterase inactivates cyclic GMP.

Question 6

describe the process of smooth muscle relaxation (NO and cGMP)

Answer 6

increased levels of calcium/mechanical shear stress activate eNOS
–> produce NO, which diffuse from endothelial cell
–> smooth muscle cell
–> activate guanylyl cell
–> produce cGMP
–> activate PKG
–> smooth muscle relaxation.

Question 7

effect of nitric oxide: cardiovascular system:

Answer 7

endothelium/vascular smooth muscle, control blood pressure, regional blood flow.

platelets: limitation of adhesion/aggregation

Question 8

effect of nitric oxide: host defence:

Answer 8

macrophages, neutrophils, leukocytes: defence against pathogens.

Question 9

effect of nitric oxide: nervous system:

Answer 9

central: neurotransmission, long term potentiation, plasticity (memory, appetite, nociception)

peripheral: neurotransmission (e.g. gastric emptying)

Question 10

effect of NO gas on BV in ventilated alveoli?

Answer 10

vasodilation. dilation of blood vessel, used to treat patients with respiratory distress syndrome.

Question 11

how does PDE inactivate cAMP and cGMP?

Answer 11

by conversion to AMP or GMP respectively

Question 12

what does PDE5 do in regards to cGMP?

Answer 12

metabolizes cGMP. PDE5 inactivates cGMP. (cGMP –> GMP)

Question 13

give example of PDE5 inhibitor, effects and indication.

Answer 13

PDE5 inhibitor. e.g. sildenafil: selective PDE5 inhibitor. cause vasodilation.

pulmonary hypertension, erectile dysfunction (Viagra)

Question 14

pulmonary arterial hypertension associated with (increase/decrease) in eNOS.

Answer 14

decrease.

Question 15

in pulmonary arterial hypertension, what are the beneficial effects of cGMP signaling pathway? (how is it obtained?)

Answer 15

obtained through inhibiting breakdown of cGMP through inhibition of PDE. (PDE5 turns cGMP to GMP)

Question 16

what is sildenafil? what is it often used to treat?

Answer 16

selective PDE5 inhibitor.

improve exercise capacity, severity of pulmonary arterial hypertension and hemodynamics in patients with pulmonary arterial hypertension.

Question 17

critical physiological role of renin-angiotensin system?

Answer 17

regulation of arterial blood pressure, renal function

Question 18

critical pathological role of renin-angiotensin system?

Answer 18

hypertension, myocardial infarction, heart failure, renal injury

Question 19

renin-angiotensin system provides therapeutic targets for management of:

Answer 19

hypertension, heart failure, renal disease.

Question 20

explain the renin-angiotensin system. name therapeutic targets as well.

Answer 20

renin (produced by kidney) act on circulating angiotensinogen
–> angiotensin I (10 amino acid peptide), processed by
–> ACE (angiotensin converting enzyme) in lungs
–> angiotensin II
–> bind to receptors AT1 and AT2.

target ACE, AT1 receptor for medicinal purposes.

Question 21

what is angiotensinogen. where is it synthesized?

Answer 21

Synthesized primarily in the liver and serves as the source of all angiotensin peptides.

Question 22

Where is angiotensinogen primarily synthesized?

Answer 22

liver

Question 23

What are some factors that stimulate the synthesis of angiotensinogen?

Answer 23

Inflammation, insulin, oestrogens, glucocorticoids, thyroid hormone, and angiotensin II.

Question 24

How can oral contraceptives containing estrogen impact angiotensinogen levels?

Answer 24

increase circulating levels of angiotensinogen and potentially induce hypertension.

Question 25

difference between angiotensin I and II?

Answer 25

angiotensin I relatively inactive. converted by ACE to angiotensin II, which is more active.

Question 26

effect of angiotensin II in terms of blood pressure?

Answer 26

vasoconstriction, leading to hypertension.

Question 27

oral contraceptives containing oestrogen can have what effect on angiotensinogen, and induce what?

Answer 27

increase circulating levels of angiotensinogen. induce hypertension.

Question 28

how does renin convert angiotensinogen to angiotensin I?

Answer 28

it is a protease that cleaves bond between residues 10 and 11 of angiotensinogen –> angiotensin I.

Question 29

what affects the rate of angiotensin II production?

Answer 29

amount of renin released by kidney.

Question 30

renin is synthesized, stored, and secreted into renal arterial circulation by ? cell.

Answer 30

granular juxtaglomerular cell.

Question 31

what do granular juxtaglomerular cells do?

Answer 31

synthesize, store, secrete renin into renal arterial circulation.

Question 32

Bosentan: what does it do? what does it target?

Answer 32

blocks effects of ET-1 at ETA and ETB receptors. antagonist. relatively low affinity for both receptors.

induce smooth muscle relaxation, bronchodilation, and vasodilation, improve exercise endurance, haemodynamics and functional class for patients with pulmonary arterial hypertension.