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LF260 Neuropharmacology > Lecture 7: Noradrenergic Transmission > Flashcards

Lecture 7: Noradrenergic Transmission Flashcards

1
Q

Why are noradrenaline and other similar substances known as monoamines?

A

Contain a monoamine group.

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2
Q

What is the difference between adrenaline and noradrenaline in terms of their release?

A

Adrenaline is a hormone released from the chromaffin cells of the adrenal medulla, while noradrenaline is a neurotransmitter.

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3
Q

Name some other examples of monoamines.

A

Dopamine and serotonin (also known as 5HT)

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4
Q

What are the subgroups of monoamines?

A

Catecholamines (also known as adrenalamines) and tryptamines.

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5
Q

What is the precursor to noradrenaline?

A

L-tyrosine, which is obtained from diets, serves as the precursor to noradrenaline.

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6
Q

What is the role of tyrosine hydroxylase in the synthesis of noradrenaline?

A
  • Rate-limiting enzyme for the synthesis of noradrenaline and dopamine
  • Present in noradrenergic (NA) and dopaminergic (DA) neurons in the chromaffin cells of the adrenal medulla.
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7
Q

How is dopamine synthesized from L-tyrosine?

A

The actions of tyrosine hydroxylase on L-tyrosine result in the formation of DOPA (dihydroxyphenylalanine).

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8
Q

What enzyme converts DOPA to dopamine?

A

DOPA decarboxylase

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9
Q

How is noradrenaline synthesized from dopamine?

A

Dopamine is enzymatically converted to noradrenaline by the enzyme β-hydroxylase, which is found in noradrenergic vesicles and terminals.

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10
Q

What enzyme mediates the synthesis of adrenaline?

A

Phenylethanolamine N-methyl transferase

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11
Q

What is the role of chromogranin A in chromaffin cells?

A
  • Chromogranin A, a protein, binds to noradrenaline and adrenaline in chromaffin cells.
  • This binding prevents the leakage of these compounds from vesicles into the cytosol, maintaining them inside the vesicles and reducing the energetic requirements of the cell.
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12
Q

What is the mechanism of action of α-methylparatyrosine?

A

Inhibits the synthesis of monoamines, including dopamine, noradrenaline, and adrenaline.

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13
Q

How do carbidopa and benserazide function in the synthesis of dopamine?

A
  • Carbidopa and benserazide inhibit the enzyme dopa decarboxylase, preventing the conversion of L-DOPA to dopamine.
  • This inhibition is crucial in the treatment of Parkinson’s disease to correct deficits in dopamine production caused by damage to neurons in the substantia nigra.
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14
Q

What is the significance of coupling L-DOPA treatment with enzyme inhibitors in Parkinson’s disease?

A
  • L-DOPA is administered as a precursor to dopamine in the treatment of Parkinson’s disease. However, its peripheral conversion to dopamine can lead to stimulatory effects on the heart.
  • Coupling L-DOPA treatment with enzyme inhibitors selectively inhibits DOPA decarboxylase in the periphery, preventing peripheral conversion of L-DOPA to dopamine and minimizing side effects.
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15
Q

How does the conversion of dopamine to noradrenaline occur?

A
  • Dopamine is converted to noradrenaline via the enzyme dopamine beta-hydroxylase.
  • While compounds like carbidopa and benserazide inhibit the conversion of L-DOPA to dopamine, they are not particularly effective inhibitors of dopamine beta-hydroxylase. Other compounds, such as disulfiram, can inhibit this enzyme.
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16
Q
  • How is the hydrogen concentration gradient built up in vesicles?
A

ATPase pumps hydrogen ions against their gradient, creating a concentration gradient. This gradient is utilized to power the uptake of monoamine neurotransmitters.

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17
Q

What effect does reserpine have on neurotransmitter uptake?

A
  • Reserpine inhibits the uptake of noradrenaline, depleting stores of noradrenaline, dopamine, and serotonin.
  • This leads to a general decrease in sympathetic function, resulting in effects such as decreased heart rate and blood pressure. Reserpine was initially used to treat hypertension.
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18
Q

What are the side effects of reserpine?

A
  • Damage to vesicles
  • Postural hypotension
  • Hypothermia
  • Sedation.
  • Reserpine’s ability to deplete monoamine neurotransmitters also led to its consideration in the monoamine theory of depression, as it can induce symptoms of depression.
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19
Q

How does α-methyl DOPA affect noradrenaline (NA) levels?

A
  • α-methyl DOPA is taken up by the uptake mechanism for NA and converted inside the cytosol to α-methyl noradrenaline (NA).
  • It is then taken up inside the vesicles, causing NA to be expelled or present in the cytosol, where it undergoes metabolism by monoamine oxidase.
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20
Q

What is the significance of α-methyl noradrenaline?

A
  • α-methyl noradrenaline, when occupying vesicles, is released instead of NA.
  • It is less potent than NA at α1 adrenoreceptors and activates α2 adrenoreceptors, which are presynaptic receptors.
    • Activation of α2 adrenoreceptors inhibits NA release, resulting in lower heart rate and blood pressure.
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21
Q

How is α-methyl DOPA used clinically?

A

Treat hypertension, including in pregnant women.

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22
Q

How does the release of noradrenaline (NA) occur?

A
  • Similar to acetylcholine, the release of NA relies on the invasion of action potentials through the synaptic cleft.
    • This activation of action potentials is carried by sodium ions.
  • Depolarization of the presynaptic terminal activates voltage-gated calcium channels → fusion of vesicles with the presynaptic membrane → release of NA into the synaptic cleft.
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23
Q

What compounds affect the release of NA?

A

The same compounds that inhibit acetylcholine release also affect the release of NA.

24
Q

How is the release of NA regulated?

A
  • The presence of α-2 adrenoceptors, which are presynaptic inhibitory autoreceptors
  • These receptors are a common feature of neurotransmitters and serve as an inhibitory feedback mechanism.
  • When activated, they inhibit calcium channels that support the release of the neurotransmitter.
25
Q

What is clonidine?

A

α-2 adrenergic receptor agonist.

26
Q

How does clonidine work?

A

Activates α-2 adrenergic receptors on the presynaptic terminal, leading to a decrease in the release of noradrenaline (NA).

27
Q

In which conditions is clonidine clinically used?

A

Clonidine is used in conditions where excessive NA release is implicated, such as hypertension (high blood pressure), Tourette’s syndrome, and menopausal flushing.

28
Q

How does enzymatic breakdown occur for acetylcholine?

A

Action of acetylcholinesterase (AChE), which breaks down ACh into acetate and choline.

29
Q

What is the mechanism of removal for monoamines like noradrenaline (NA)?

A

Removed from the synaptic cleft through a process of uptake or transport-mediated removal.

30
Q

What are the two uptake mechanisms for monoamines?

A
  • NET- Norepinephrine Transporter: presynaptically
  • EMT - Extra-neuronal monoamine transporter
31
Q

Describe EMT (Extra-Neuronal Monoamine Transporter).

A

EMT is a non-neuronal transporter with low affinity for monoamines. It is found in a variety of tissues.

32
Q

Describe NET (Norepinephrine Transporter).

A

NET is a presynaptic transporter with high affinity for monoamines, especially noradrenaline. It is a target for various drugs, and inhibiting this pump increases the presence of NA and other monoamines in the synaptic cleft.

33
Q

What is the role of MAO (monoamine oxidase)?

A
  • Enzyme responsible for the breakdown of monoamine neurotransmitters such as serotonin, dopamine, and noradrenaline.
  • Inhibitors of MAO were used in early treatments for depression.
34
Q

What is COMT (catechol-o-methyl transferase)?

A
  • Enzyme involved in the breakdown of catecholamines, including dopamine, epinephrine, and norepinephrine.
  • Inhibitors of COMT are targeted for the treatment of Parkinson’s disease and can be used as a therapy.
35
Q

What is the significance of ADH (aldehyde dehydrogenase)?

A

ADH, or aldehyde dehydrogenase, is an enzyme involved in the metabolism of alcohol. It converts toxic aldehydes produced during alcohol metabolism into non-toxic substances.

36
Q

What are the two broad classes of adrenoceptors?

A

α-adrenoceptors and β-adrenoceptors

37
Q

Where are α1 receptors typically found, and what is their function?

A

Vascular smooth muscle and vas deferens smooth muscle, where they induce contraction.

38
Q

Where are α2 receptors typically found, and what is their function?

A
  • Adrenergic nerve terminals.
  • They play a role in decreasing the production and release of noradrenaline (NA).
39
Q

What subtypes are included in the β-adrenoceptors?

A

β1, β2, and β3.

40
Q

Where are β1 receptors typically found, and what is their function?

A

Typically found in cardiac muscle, where they increase heart rate and the force of contractions.

41
Q

Where are β2 receptors typically found, and what is their function?

A

Typically found in cardiac blood vessels, skeletal muscle blood vessels, and bronchial smooth muscle. They result in dilation and relaxation.

42
Q

Where are β3 receptors typically found, and what is their function?

A

Typically found in adipose tissue (but not in the brain), where they promote lipolysis.

43
Q

What are the signal transduction mechanisms associated with α1 adrenoceptors?

A

α1 adrenoceptors activate Gαq, leading to the release of protein kinase C (PKC) and calcium (Ca) from internal stores. This signaling pathway results in the contraction of vascular smooth muscle.

44
Q

What are the signal transduction mechanisms associated with α2 adrenoceptors?

A

α2 adrenoceptors are coupled to Gαi, which leads to a reduction in cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity. This pathway also involves a decrease in Gβγ, which inhibits voltage-gated calcium channels. Ultimately, activation of α2 adrenoceptors results in the reduction of insulin and noradrenaline (NA) release.

45
Q

What are the signal transduction mechanisms associated with β1, β2, and β3 adrenoceptors?

A

β1, β2, and β3 adrenoceptors stimulate Gαs, leading to increased cAMP and PKA activity, which is opposite to the signaling pathway initiated by Gαi. This activation results in increased cardiac output, dilation/relaxation of smooth muscle, and promotion of lipolysis.

46
Q

What are some clinical uses of agonists targeting adrenergic receptors?

A
  • Sympathomimetics, which mimic the activation of the sympathetic nervous system, are utilized for various clinical purposes.
  • Noradrenaline and adrenaline can be employed to counteract the effects of conditions such as shock, cardiac arrest, and anaphylactic shock, which often involve a profound decrease in blood pressure.
  • Salbutamol acts on β2 adrenergic receptors, resulting in smooth muscle relaxation. It is commonly used in the treatment of asthma and inhibition of premature labor.
47
Q

What are indirectly acting sympathomimetics, and how do they work?

A

Indirectly acting sympathomimetics do not directly target adrenergic receptors but instead enhance the effects of endogenous catecholamines like norepinephrine.

48
Q

Tyramine

A
  • Stimulates the release of norepinephrine.
  • It is taken up by the norepinephrine synaptic terminal via the norepinephrine transporter (NET).
  • Displaces norepinephrine from the uptake mechanism, leading to the accumulation of norepinephrine in the cytosol.
  • Tyramine is obtained from our diet.
49
Q

Cheese reaction

A
  • Tyramine present in food is metabolized by monoamine oxidase (MAO).
  • Some antidepressants (such as phenelzine) inhibit MAO.
  • The combination of tyramine-rich foods and MAO inhibitors can result in the cheese reaction.
  • The cheese reaction is characterized by an acute increase in blood pressure.
50
Q

How are the actions of norepinephrine (NA) on blood pressure mediated?

A

The actions of norepinephrine on blood pressure are primarily mediated through the α-1 adrenoreceptor.

51
Q

Prazosin

A
  • Mechanism: Deactivates the α-1 adrenoreceptor, preventing constriction of blood vessels.
  • Result: Decrease in blood pressure.
  • Benefits: Fewer side effects due to its selectivity for the α-1 receptor.
  • Impact on baroreceptor reflex: Prazosin does not trigger the baroreceptor reflex, where a drop in blood pressure typically leads to an increase in heart rate.
52
Q

Labetalol

A
  • Mixed antagonist:
    • Mechanism: Blocks both α and β adrenoceptors.
    • Result: Decrease in blood pressure via α1 blockade.
    • Additional effect: β1 blockade counteracts the typical increase in heart rate seen with α1 antagonists.
53
Q

Propranolol

A
  • Type: Non-selective β-adrenoceptor blocker, blocking all β-adrenoceptors.
  • Mechanism: Decreases heart rate, blood pressure, and cardiac output via β1 receptor blockade, reducing strain on the heart.
  • Consequences:
    • Bronchoconstriction: Due to β2 blockade, making it unsuitable for individuals with asthma.
  • Clinical Uses:
    • Angina
    • Dysrhythmias
54
Q

Atenolol

A
  • Type: Cardioselective β1-adrenoceptor blocker.
  • Mechanism: Reduces heart rate, blood pressure, and cardiac output by selectively blocking β1 receptors, alleviating strain on the heart.
  • Clinical use: hypertension
55
Q

Pindolol

A
  • Type: Partial agonist, meaning it activates receptors to a lesser extent than full agonists.
  • Mechanism: Reduces the effects of naturally occurring agonists (such as adrenaline or norepinephrine), preventing excessive constriction of blood pressure.
  • Clinical Use: Hypertension.

LF260 Neuropharmacology (14 decks)

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