NA release Flashcards
What are the two main sources of NA?
sympathetic nerve terminals and the adrenal medulla
NAD is released from the post-ganglionic neurone
Where is adrenaline found?
the inner part of the AM
What does the ANS regulate?
heart rate and force; SM tone, all exocrine and some endocrine secretions
Nerve terminal variscosities
Swellings where neurotransmitter vesicles are stored (looks like beads on a string)
Neurones in the ANS
- Para: LONGER PRE
* Symp: LONGER POST
Synthesis pathway of NA and A
TYROSINE (Tyrosine hydroxylase) –> Dihydroxyphenylalanine (DOPA) = RDS, feedback inhibition by NA
DOPA (DOPA decarboxylase) –> Dopamine
Dopamine (Dopamine- B- hydroxylase) –> NA
NA (Phenylethanolamine N-methyl transferase) –> Adrenaline
Inhibitor of tyrosine hydroxylase?
a-methyltyrosine (blocks AS)
Inhibitor of DOPA decarboxylase?
Carbidopa
Inhibitor of Dopamine B-hydroxylase?
nepicastat
Where is PNMT located?
In A cells of AM
Parkinson’s
- Treatment by L-dopa
- People who have Parkinson’s disease don’t produce enough dopamine in the brain.
- If you give someone DOPA, this enzymatic pathway is still active in the periphery, meaning much of the DOPA will still be broken down
- DOPA can cross BB barrier, Dopamine cannot
- Whenever DOPA is given to a patient, given with carbidopa (doesn’t enter the brain) and therefore reduces unwanted peripheral actions of administered L-dopa.
Other drugs affecting NA synthesis?
Methyldopa: taken up by sympathetic neurones; converted to a-methylNA; displaces NA from vesicles therefore acts as a ‘false’ transmitter. Uses: hypertension in pregnancy
Storage of NA and A in adrenal glands?
- NAd and Ad are not free in the cytoplasm but are stored in subcellular-membrane limited particles inside chromaffin granules
- Packed into vesicles
- VMAT: Takes the catecholamines such as Dopamine into the vesicle. This process needs energy which comes from hydrogen ions (uses pH gradient); low pH in vesicles (ATPase)
- VNUT: Transporters of ATP into vesicles
Reserpine
- Inhibits VMAT catecholamine run down slowly as amines leak out (5% of normal after 12 hours)
- Used in the past to treat hypertension (SNS drives HR to increase)
- Fallen out of chemical use: not specific i.e effects SNS and CNS; effects serotonin: people often developed depression
Exocytosis from sympathetic nerves?
- Ca2+ entry increase in concentration of free Ca2+ activates Ca2+ sensitive proteins that initiate the process of exocytosis
Botulinum toxin effects exocytosis
• Many of the nerve terminals have receptors on them for a whole variety of different substances: Pre-junctional receptors; regulate the release of NA by inhibiting or exciting it.
• Best well known pre-junctional receptors are receptors for NA itself.
• When NA is released can act back on the nerve terminals where there are a2 adrenoreceptors
• A-2 adrenoreceptors act to inhibit further neurotransmitter release (negative feedback)
• A lot of activity= a lot of inhibition.
• A lot of early evidence for this:
• Blocking a-2 receptors with an antagonist, amount of NA released will be increased (can be seen by using radioactive labelled NA.)
Regulation of release: pre-junctional modulation
- Ach: INHIBITS release; via muscarinic receptors; produces lateral inhibition from PS nerves
- Angiotensin II: facilitates release via AT1 receptor
Morphine (opiod)
- Potent analgesic, but with important autonomic SE: constipation, pupillary dilation
- Autonomic SE are through the prejunctional release of NT release
- Opiod receptors are present on most autonomic nerve terminals where they inhibit NT release. Inhibit Enteric NS increases activity within gut wall.
Termination of A and NA action
- 2 stages: uptake (into sympathetic NT or other cells); degradation via intracellular enzymes
- 2 distinct uptake systems: Neuronal or non-neuronal (both are AT mechanisms)
Neuronal uptake and inhibitors
• High affinity for NA; low maximal rate of uptake
• Co-transports Na+ and Cl-
• Inhibited by: Cocaine; tricyclic antidepressants
Inhibitors of NA uptake
• NAT inhibitors ENHANCE the effects of the CNS; NAT is closely related to dopamine and serotonin transporters (DAT and SERT)
• Desipramine: Tricyclic antidepressant; major action on CNS; adverse effects are tachycardia, dysrhythmia
• Cocaine: Euphoria and excitement; tachycardia and increased BP; local anaesthetic
Non-neuronal
• Non-neuronal (e.g cardiac, SM, endothelium)
• Low affinity for NA; high maximal rate of uptake
• Not particularly selective for NA
Inhibited by: Normetanephrine, steroid hormones
Metabolic degradation of CC’s
- 2 main intracellular enzymes, in various tissues: MAO; catechol-O-methyl transferase (COMT)
- 2 other enzymes involved: aldehyde dehydrogenase (ADH); mainly in periphery; aldehyde reductase (AR); mainly in CNS
MAO
- Bound to surface of M; found in many tissues in including NT
- Converts catecholamines to aldehydes aldehydes then metabolised by AD or AR
- Inhibited by several drugs which are used therapeutically for their effects on the CNS (treatment of depression)
MAOI
- Most block MAO IRREVERSIBLY; used clinically as antidepressants increases levels of NA, dopamine, 5-HT in the brain and peripheral tissues
- Adverse effects include: restlessness, insomnia, weight gain
- Examples: Phenelzine
Catechol-O-methyl transferase (COMT)
- Found in many tissues, including NT; cytoplasmic
- Converts CC’s to methyl group derivatives by transferring a methyl group to one of the catechol –OH groups
- Acts not only on CC’s but also on the products of other degradative reactions (MAO)
VMA
- Main final metabolite of A and NA; excreted in urine
- Urinary VMA used as a diagnostic test for a rare tumour of chromaffin tissue (AM) that secretes high levels of CC’s resulting in elevated BP
Noradrenergic neuron blocking drugs
- Inhibit NA release from sympathetic NT (e.g guanethidine)
- Enter NT and inhibit AP’s via ion channels or exocytotic proteins
- No longer clinically used: severe adverse effects e.g failure of ejactulation, diarrhoea
Indirectly acting sympathetic amines
- Amphetamine, tyramine
- Struturally related to NA; transported into NT and into vesicles
- Displace NA, which leaks out via NAT
- Longer lasting effects mimic those of NA: e.g vasoconstriction
- Cause the release of NA, activates its receptors and mimicks sympathetic effects.
- INDIRECTLY ACTING as they themselves don’t activate receptors but cause the release of NA
