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Pharmacology GPP > NORADRENALINE: SYNTHESIS, STORAGE, RELEASE, FATE & METABOLISM > Flashcards

NORADRENALINE: SYNTHESIS, STORAGE, RELEASE, FATE & METABOLISM Flashcards

1
Q

How is cholesterol produced in the adrenal cortex

A

• Cholesterol-processing enzymes in sER, inner mitochondria membrane
– Tubulovesicular mitochondria.
• Much inner membrane surface area
• MuchP450s
• Parenchymal cells can produce cholesterol de novo
– Mainly endocytosis of LDL
– Cholesterol-rich lipid droplets in cytoplasm
• Capsule + 3 cell layers
11

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2
Q

What cells of the adrenal cortex can produce cholesterol de novo

A

Parenchymal cells can produce cholesterol de novo
– Mainly endocytosis of LDL
– Cholesterol-rich lipid droplets in cytoplasm

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3
Q

What’s the adrenal cortex made of

A

Capsule + 3 cell layers

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4
Q

What part of the adrenal half is a modified sympathetic ganglion

A

Adrenal medulla

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5
Q

Function of adrenal medulla

A

– Release catecholamines to ECF

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6
Q

Describe the cells of the adrenal medulla

A

They’re called pheochromocytes
– Axonless secretory cells
– Two cell subpopulations
• Same cell population under different physiologic states – Concent cortisol exposure
• Norepinephrine (noradrenaline) producing cells
• Epinephrine (adrenaline) producing cells

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7
Q

How do pheochromocytes exceed their cells to the ECF

A

Secrete products from granulesECF by exocytosis

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8
Q

Does the adrenal medulla contain post ganglionic fiber

A

• Adrenal medulla is a modified part of sympathetic nervous system
– Modified sympathetic ganglion that does not give rise to postganglionic fibers

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9
Q

What stimulates the release of the medullary hormones into the circulation

A

– Stimulation of preganglionic fiber prompts secretion of hormones into blood
•About. 20% of hormone release is norepinephrine
•About 80% of hormone released is epinephrine(adrenaline)

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10
Q

Describe the similarities between a normal sympathetic ganglion and an adrenal medulla

A

In a normal sympathetic ganglion, at the pre synaptic cleft, Ach is produce and the. At the post ganglionic cleft, Epinephrine and norepinephrine are produced

But In the adrenal medulla, the presynaptic ganglion brings Ach into the medulla where Epinephrine and norepinephrine are produced, in the absence of moving to a post synaptic cleft, the catecholamimes are secreted into the ECF directly

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11
Q

What’s the primary stimulus for increased adrenomedullary secretion

A

Stress

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12
Q

Epinephrine and norepinephrine are released into the ECF by exocytosis of what granules

A

– Secreted into blood by exocytosis of chromaffin granules

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13
Q

What are the functions of epinephrine

A

– Maintenance of arterial blood pressure
– Increases blood glucose and blood fatty acids

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14
Q

What’s the stimulus for Epinephrine secretion

A

Stress (psychological reactions), elevated sound levels, intense light, low blood sugar levels

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15
Q

Describe the synthesis of epinephrine

A

Tyrosine
|Tyrosine hydroxylase
|
DOPA
|DOPA decarboxylase
|
Dopamine
|Dopamine B hydroxylase
|
NE
|PNMT
|
Epinephrine

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16
Q

Conc of L-dopa in the plasma

A

1-1.5 mg/dL

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17
Q

How is L- Dopa transferred into cells

A

Active transport into cells

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18
Q

How many enzymes convert L-Dooa into epinephrine

A

4 enzymes

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19
Q

What’s the plasma ratio of norepinephrine to epinephrine

A

ratio 8:2

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20
Q

Explain the conversion of tyrosine to adrenaline

A

Phenylalanine
| phenylalanine hydroxylase
|
Tyrosine
|tyrosine hydroxylase
|
L Dopa
|Dopa decarboxylase
|
Dopamine
|Dopamine B hydroxylase
|
Norepinephrine
|phenylethanolamine N methyltransferase
|
Epinephrine

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21
Q

I’m what step of the synthesis of epinephrine is tetrahydrobiopterin (O2) converted to dihydobiopterin (H2O)

A

Tyrosine to L Dopa (tyrosine hydroxylase)

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22
Q

In what step in the synthesis of epinephrine is S-adenosylhomocystein converted to S-adenosylmethione

A

Norepinephrine to epinephrine (phenylethanolamine N methyl transferase)

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23
Q

What’s the % to which catecholamines are produced

A

Epinephrine 80%
Norepinephrine 20%

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24
Q

What are the adrenergic receptors

A

• α1β1: excitatory
• α2β2: inhibitory

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25
Q

What’s the location of the alpha 1 receptor

A

Most synaptic target cells

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26
Q

What’s the location of the alpha 2 receptor

A

Digestive system

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27
Q

What’s the location of the beta 1 receptor

A

Heart

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28
Q

What’s the location of the beta 2 receptor

A

Skeletal muscle
Smooth muscle of some blood vessels
Organs

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29
Q

What has more affinity for alpha 1 receptor

A

NE

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30
Q

What has more affinity for alpha 2 receptor

A

NE

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31
Q

What has more affinity for beta 1 receptor

A

NE and Epinephrine

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32
Q

What has more affinity for beta 2 receptor

A

Epinephrine

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33
Q

What type of response is elicited from the alpha 1 receptor

A

Generalised arteriolar constriction

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34
Q

What type of action is elicited by the alpha 2 receptor

A

Decreased motility of the digestive tract

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35
Q

Hat kind of action is elicited by the beta 1 receptor

A

Increased rate and strength of cardiac cells

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36
Q

What kind of action is elicited by the Beta 2 receptor

A

Breakdown of glycogen in skeletal muscle
Bronchioles dilation and arteriolar vasodilation in skeletal muscle and heart
(Decreased smooth muscle constriction)

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37
Q

What’s the function of tyrosine hydroxylase

A

Ring hydroxylation to L-DOPA (L-Dihydroxy-PhenylAlanine)

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38
Q

What cofactor does tyrosine hydroxylase contain

A

Contains Fe2+; tetrahydrobiopterin cofactor

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39
Q

What regulates tyrosine hydroxylase

A

Activity regulated by preganglionic nerves
– Get phosph’n PKA, PKC and calmodulin-dependent kinases

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40
Q

What’s the long term stimulation of tyrosine hydroxylase

A

upregulation of transcription, translation

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41
Q

What inhibits the production of tyrosine hydroxylase

A

Increased L-DOPA

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42
Q

What’s another name for Dopa decarboxylase

A

L-aromatic amino acid decarboxylase

43
Q

What’s the go factor for DOPA decarboxylase

A

Pyridoxal phosphate cofactor

44
Q

Where is The DOPA decarboxylase end product found

A

In the CNS

45
Q

Where is DOPA decarboxylase stored and how is it released

A

• Stored in secretory vesicles
– Enter by active transport
– MVATs (Vesicular MonoAmine Transporters)

46
Q

What provides the side chain hydroxylation to become noradrenaline

A

3) Dopamine beta Hydroxylase

47
Q

What cofactors do dopamine beta hydroxylase contain

A

Contains Cu; Vit C cofactor

48
Q

Where does the reaction of dopamine bet hydroxylase occur

A

• Rxn w/in secretory vesicle

49
Q

Where does the action of dopamine beta hydroxylase take place

A

• Rxn w/in secretory vesicle

50
Q

Where is the end product of dopamine beta hydroxylase

A

• End prod in symp. nerves, most central catecholaminergic neural tracts

51
Q

What’s the function of Phenylethanolamine N- MethylTransferase (PNMT

A

N-methylation to epinephrine

52
Q

What’s the S donor for phenylethanolamine N methyl transferase

A

S- Adenosylmethionine

53
Q

Where does the action of phylehanolamine N methyl transferase occur

A

Cytoplasm

54
Q

What happens to norepinephrine and epinephrine after the action of phenylethanolamine n methyl transferase

A

– Norepinephrine leaves vesicle
• Passive transport
• Concent gradient
– Epinephrine must reenter secretory vesicle
• Active transport

55
Q

What does the expression of PNMT depend on

A

• Expression depends on high local cortisol
– From adrenal cortex
– Through sinusoid system

56
Q

Explain Transcriptional activation of PNMT

A

Transcriptional activation of PNMT gene through ligand-activated glucocorticoid receptor
– Also other transcription factors

57
Q

What stimulates PMNT

A

Glucocorticoids

58
Q

What’s the effect of adrenaline on PMNT

A

Feedback inhibition

59
Q

What other places can PMNT be found

A

Other than adrenal medulla

kidney, lung, pancreas

60
Q

Function on non specific NMT

A

Contributes to peripheral conversion norepi. to epi.

61
Q

Where are cathecolamine stored

A

Secretory vesicles

62
Q

How are cathecholamines transported

A

Active transport via VMATs
– ATP-driven proton pump
– In vesicle membranes
– pH, electrical gradient
– Antiporte

63
Q

What are the 12 transmembrane helical segments found in secretory vesicles

A

Related to plasma membrane monoamine transporters

64
Q

How are Ach released from presynaptic ganglion

A

Nicotinic receptors
Get depolarization of pheochromocytes
act’n voltage-gated Ca2+ channels influx Ca2+
exocytosis of secretory vesicles
• Chromogranins, DBH, ATP, other peptides released

65
Q

What other things are realeased at the presynaptic vesicle along with Ach

A

Chromogranins, DBH, ATP, other peptides released

66
Q

What can cathecolamine not penetrate

A

• BBB
• Fetus

67
Q

How does fetus get catecholamines

A

Fetal production (mostly norepi) through fetal zone
• Impt in intrauterine life (cardiovascular responses)
• Large
• Placenta expresses catecholamine degrading enzymes

68
Q

What catecholamine is more in featal life

A

NE

69
Q

How does NE get degraded I’m featal life

A

Placental norepi. transporter
– Delivers circulating fetal catechol’s for degrad’n

70
Q

What’s the half life of catecholamines

A

• Short-lived molecules
– 10 sec to 1.7 min

71
Q

What are most catecholamines associated with

A

• 50-60% associated with albumin

72
Q

How are catecholamines eliminated

A

– At synapse, ISF near sympathetic neurons
• Reuptake into nerve terminals
• Reenter vesicles via VMAT OR
• Become degraded by monoamine oxidase (MAO, MAOIs bind to MAO for inhibition)
– In target cells
• Degraded by Catechol-O-MethylTransferase (COMT)
– 5% directly filtered into urine

73
Q

When epinephrine is acted upon by COMT, what does it become

A

(At the target site)
It becomes metanephrine

Then becomes metanephrine sulfate or glucoronide

74
Q

Where does MAO degrade catecholamine

A

At the synapse

75
Q

Where does COMT degrade catecholamine

A

At the target site

76
Q

When MAO acts of epinephrine, what does it become

A

(At the synapse)
3,4 dihydroxy mandelic acid

77
Q

How is 3,4 dihydroxymandelic acid degraded

A

Acted on by COMT to give 3, methoxy 4, hydroxymadelic acid

aka vanillymandelic acid

78
Q

How else can 3, methoxy 4, hydroxy mandelic acid (vanillymandelic acid) be gotten other than degradation of 3,4 dihydroxymandelic acid ( by COMT)

A

By degradation of metanephrine by MAO

79
Q

How do you remember the break down of epinephrine and where each enzyme works on

A

On a straight line(vertically) it’s worked on by COMT (at target site)

So from epinephrine to metanephrine
And from 3,4 dihydroxymandelic acid to 3,methoxy 4, hydroxylase mandelic acid

Are both by COMT

By on a horizontal line, it’s by MAO (at synapse)

So from epinephrine to 3,4 dihydroxymandelic acid
And from metanephrine to 3, methyl 4 hydroxymandelic acid

Are both by MAO

80
Q

Where is MAO found

A

Outer mitochondrial membrane

81
Q

What are the substrates of MAO

A

also include serotonin, histamine

82
Q

How does MAO work

A

Oxidizes amino grp to aldehydes

– Further oxidation by nonspecific aldehyde dehydrogenase

83
Q

What is the ultimate product of MAO

A

Ultimate production of dihydroxymandelic acid (DOMA)

84
Q

What are the types of MAO

A

– MAO-A and MAO-B

85
Q

What kind of degradation does COMT do

A

extraneuronal degradation

86
Q

What is the methyl donor for COMT

A

S-Adenosyl methionine

87
Q

What kind of catecholamine is COMT important for degrading

A

Important to circulating catecholamines

88
Q

How does catecholamine get its final conjunction

A

Sulfate, glucuronate in liver, gut
– Excretion through urine

89
Q

What are the sympathoadrenal functions

A

1) Catecholamines regulate intermediary metabolism.
- Carbohydrate metabolism (β-AR ): blood glucose levels increased
- Fat metabolism (β-AR ): activates a hormone-sensitive lipase, triglyceride lipasemetabolizes fats into fatty acids (FFAs) and glycerol
- Protein metabolism (β-AR ): decreases the release of amino acids from skeletal muscle
2) The sympathetic nervous system regulates thermogenesis.
- Shivering thermogenesis:
- Nonshivering (chemical) thermogenesis: brown adipose tissue in the rat
3) Adrenergic receptors mediate cardiovascular responses to stress (β-AR )
4) physiologic implications

90
Q

What are the physiological implications of the sympathoadrenal catecholamines

A

• General: activates fight/flight mechanisms. – Mobilizes energy, redist’s blood
• Opposes parasympathetic system
– Promotes digestion, storage of energy
– BUT distinct target cell pop’ns w/in organs
• Many targets; overall
– Increase cardiac output, blood pressure
– Bronchodilationmatched perfusion w/ increased ventilation
– Blood diverted from viscera and skin to muscle
• Retain blood to brain
– Mobilize fuel from energy stores

91
Q

Is PNMT Involved in the synthesis of NE

A

No

92
Q

Where is PNMT found

A

Adrenal medulla

93
Q

How is NE stored

A

In vesicles carried by VMAT

94
Q

What synthesis of Epinephrine occurs before entry into the vesicles

A

Tyrosine - - - - -> Dopamine

95
Q

What synthesis of epinephrine occurs in the vesicles

A

Dopamine’s.- - - - - -> Epinephrine

96
Q

Describe the release of Epinephrine

A

• AP goes through the membrane
• Once AP gets to the axon, it opens up Ca2+ gated channels and causes an influx
• The excess Ca2+ pulls the vesicle to the end of the membrane
The vesicle fuses to the membrane, exocytosis occurs and Epinephrine is released

97
Q

How does Epinephrine carry out its functions

A

By binding to adrenergic receptors

98
Q

Describe the metabolism of epinephrine

A

It either goes back into the neuron(reuptake) and metabolized by MAO

Or it’s metabolized by COMT at the liver(target organ)

99
Q

What drug inhibits the synthesis of Epinephrine

A

Methyl tyrosine inhibits conversion of tyrosine to DOPA

100
Q

What inhibits the storage of epinephrine

A

Reserpine blocks VMAT from taking epinephrine

101
Q

What blocks the release of epinephrine

A

Guanethidine and Bratylium

102
Q

What stimulates the release of epinephrine

A

Amphethamine

103
Q

What inhibits the metabolism of epinephrine

A

MAOI
And COMT Inhibitors

104
Q

What inhibits the reuptake of NE

A

Cocaine
Tricyclic antidepressants

Pharmacology GPP (5 decks)

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