lecture 7 Chemical mediators 2 Flashcards
Noradrenaline (NA):
Is a cathecolamine
Is the main neurotransmitter in the sympathetic nervous system
Found both in the periphery and CNS
Is released from varicosities on adrenergic neurones.
Is also released by the adrenal medulla along with adrenaline (Ad).
NA and Ad both act on adrenoceptors and mediate a wide range of effects.
CATECHOLAMINES
Catecholamines are compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side-chain.
pharmacologically the most important catecholamines are :
Noradrenaline (norepinephrine), a transmitter released by sympathetic nerve terminals
Adrenaline (epinephrine), a hormone secreted by the adrenal medulla
Dopamine, the metabolic precursor of noradrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system
Isoproterenol (previously isoprenaline), a synthetic derivative of noradrenaline, not present in the body
Noradrenaline
manufactured in terminal and put into vesicles
After release it can bind to α/β receptors
A specific ‘reuptake’ mechanism exists for NAdr, taking it back into the pre-synaptic cell where it is broken down by MAO (mono-amine oxidase) enzyme.
Recycling then occurs.
in the adrenal medulla what is noradrenaline converted to
adrenaline by phenylethanolamine N-methyl transferase (PNMT).
Transmitter storage:
Noradrenaline is stored at high concentration in synaptic vesicles, together with ATP, chromogranin and DBH (dopamine β-hydroxylase), all of which are released by exocytosis.
Transport of noradrenaline into vesicles occurs by a reserpine-sensitive transporter.
Noradrenaline content of cytosol is normally low due to monoamine oxidase in nerve terminals.
Transmitter release:
Occurs normally by Ca2+-mediated exocytosis from varicosities on the terminal network.
Non-exocytotic release occurs in response to indirectly acting sympathomimetic drugs (e.g. amphetamine), which displace noradrenaline from vesicles.
Noradrenaline escapes via uptake 1 (reverse transport/neuronal uptake).
Noradrenaline release is controlled by autoinhibitory feedback mediated by α2 receptors.
Transmitter action is terminated:
Mainly by transporter-mediated reuptake of noradrenaline into nerve terminals (uptake 1), to a lesser extend also by uptake 2 (extraneuronal uptake).
NA is then degraded by the enzyme monoamine oxidase (MAO) or cathecol-O-methyl transferase (COMT)
Uptake 1 is blocked by tricyclic antidepressant drugs and cocaine.
Noradrenaline receptors:
All belong to G-protein-coupled receptors.
There are two main groups of adrenergic receptors:
α and β, with several subtypes.
Alpha receptors
Have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor).
Phenylephrine is a selective agonist of the α receptor.
α1 receptors are coupled to PLC activation causing breakdown of membrane phosphoinositides to inisitol phosphates leading to mobilisation of Ca2+.
Activation of α1 receptors causes contraction of smooth muscle cells.
Locations of α1 receptors : For example, blood vessels of gut and skin, sphincters of bladder and gut.
receptors
Coupled to adenylate cyclase.
Location: Nerve endings, isles of pancreas and platelets
Mainly cause inhibition by inhibiting transmitter release, platelet aggregation.
α-Adrenoceptors:
Order of potency:
Agonists: NA ≥Ad»Isoprenaline
Antagonist: Phentolamine (competitive)
β receptors have the subtypes
β1 ( heart), increased cardiac rate and force
β2 (blood vessels of skeletal muscles, bronchi), bronchodilatation, vasodilatation, relaxation of visceral smooth muscle, hepatic glycogenolysis and muscle tremor
β3 (liver, fat/adipose tissue), lipolysis. .
All three are linked to Gs proteins, which in turn are linked to adenylyl cyclase.
Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP and also protein kinase A (PKA).
