Noradrenaline Synthesis, Release and Degradation

Question 1

Why is autonomic pharmacology important?

Answer 1

• ANS innervates most viscera (organs)
• Unlike CNS, not protected by blood-brain barrier so. is exposed to many chemical compounds
• widespread therapeutic use
• important toxicology
• similar methods and mechanisms of transmission in multiple different tissues

Question 2

What is the autonomic nervous system?

Answer 2

• part of the peripheral nervous system that conveys all outputs from the CNS to the rest of the body, except the motor innervation of skeletal muscle
• largely outside voluntary control
• 3 divisions: sympathetic, parasympathetic and enteric (intrinsic system within the wall of the gut)

Question 3

What processes does the autonomic system regulate?

Answer 3

• smooth muscle tone
• all exocrine secretions
• some endocrine secretions
• heart rate and force
• certain metabolic porcesses

Question 4

What’s the difference between endocrine and exocrine?

Answer 4

• endocrine glands secrete hormones directly into the blood

- exocrine glands secretes its product into ducts that lead to the target tissue

Question 5

What is the sympathetic action on the iris?

Answer 5

pupil dilation

Question 6

What is the sympathetic action on the salivary glands?

Answer 6

increase salivation

Question 7

What is the sympathetic action on the oral/nasal mucosa?

Answer 7

reduce mucus

Question 8

What is the sympathetic action on the heart?

Answer 8

increase rate and force

Question 9

What is the sympathetic action on the lung?

Answer 9

dilate bronchial muscle

Question 10

What is the sympathetic action on the gut?

Answer 10

reduce motility, increase sphincter tone

Question 11

What is the sympathetic action on the liver?

Answer 11

convert glycogen to glucose

Question 12

What is the sympathetic action on the adrenal medulla?

Answer 12

secrete adrenaline

Question 13

What is the sympathetic action on the bladder?

Answer 13

wall relaxed, sphincter closed

Question 14

How do you synthesise noradrenaline and adrenaline?

Answer 14

1. Tyrosine is converted to dihydroxyphenylalanine (DOPA) using tyrosine hydroxyls
2. DOPA is converted to dopamine using DOPA decarboxylase
3. Dopamine is converted to noradrenaline using dopamine-beta-hydroxylase
4. noradrenaline is converted into adrenaline using phenylethanolamine N-methyl transferase

Question 15

What is the rate limiting step in the production of adrenaline?

Answer 15

tyrosine hydroxyls

Question 16

What uses feedback inhibition on tyrosine hydroxyls?

Answer 16

NAd

Question 17

If you want info on inhibitors for these reactions

Answer 17

look on slides

Question 18

What is Ad and NAd stored in?

Answer 18

chromaffin granules (found in neurotransmitter vesicles within the adrenal gland and the nerve terminals)

Question 19

What is the main enzyme that packages NAd or dopamine into the vesicles?

Answer 19

VMAT

Question 20

How does VMAT work?

Answer 20

-using the electrochemical gradient of H+ to move dopamine into the vesicles (H+ grad maintained by a pump)

Question 21

What happens once the dopamine is inside the vesicles?

Answer 21

can be converted into noradrenaline. by dopamine dehydroxylase

Question 22

Can VMAT transport noradrenaline into the vesicle?

Answer 22

yes

Question 23

What inhibits the VMAT transporter?

Answer 23

reserpine

Question 24

Whats the PH like inside the vesicle?

Answer 24

low (so H+ moves out as dopamine moves in)

Question 25

Why is reserpine not used today?

Answer 25

too many side effects

Question 26

Describe how exocytosis from sympathetic nerves works

Answer 26

1. arrival of action potential causes depolarisation of varicosity 2. Ca2+ entry causes an increase in the conc of free Ca2+ in the varicosity 3. This activates Ca2+ sensitive proteins that initiate the process of expocytosis

Question 27

How is the release of neurotransmitter regulated?

Answer 27

- sympathetic nerve terminals contain many different receptors for different substances - a variety of substances can act on the receptors to regulate release either by facilitating or inhibiting release

Question 28

What can happen once noradrenaline is released?

Answer 28

can act locally on presynaptic receptors to inhibit its own release and the release of ATP using α2-adrenoceptors

Question 29

What other factors can regulate the release of noradrenaline?

Answer 29

- ACh-inhibits release via muscarinic receptors - Adenosine-inhibits - Opiods- inhibit release - Angiotensin II- facilitates release

Question 30

What are the two ways of catecholamine uptake?

Answer 30

-neuronal -non-neuronal (both active transport mechanisms)

Question 31

How is catecholamines taken up neuronally?

Answer 31

- second active transporter NAT | - cotransports Na+, Cl- and catecholamine

Question 32

What is the main mechanism for terminating the actions of NAd?

Answer 32

NAT

Question 33

What is NAT inhibited by?

Answer 33

- cocaine - tricyclic antidepressants - phenolxybezamine

Question 34

What is cocaine an inhibitor of?

Answer 34

-catecholamine transporters, DAT, SERT and NAT

Question 35

How does non-neuronal uptake occur?

Answer 35

taken up by cardiac & smooth muscle and endothelium

Question 36

What are the two main intracellular enzymes used in the metabolic breakdown of catecholamines?

Answer 36

- monoamine oxidase (MAO) | - catechol-o-methyl transferase (COMT)

Question 37

Where is MAO found?

Answer 37

in many tissues including nerve terminals bound to the mitochondria

Question 38

What does MAO convert catecholamines into?

Answer 38

aldehydes

Question 39

What happens to the aldehydes?

Answer 39

metabolised by aldehyde dehydrogenase or aldehyde reductase

Question 40

What are MAO inhibitors used for, clinically?

Answer 40

anti-depressents

Question 41

How does COMT work?

Answer 41

-converst catecholamines to methoxy derivatives by transferring a methyl group to one of the catechol OH groups

Question 42

Whats the main final metabolite of Ad and NAd?

Answer 42

VMA

Question 43

What are noradrenergic neurone blocking drugs?

Answer 43

inhibit noradrenaline release from sympathetic nerve terminals

Question 44

What are some examples of indirectly acting sympathetic amines?

Answer 44

- amphetamine - ephedrine - tyramine

Question 45

How does amphetamine work?

Answer 45

- structurally related to noradrenaline - transported into NAT and into vesicles - displaces noradrenaline which leaks out via NAT - similar effect on dopamine - effect is long-lasting