Adrenergic
Transmission
·
Synthesis, metabolism
and excretion.
·
Adrenoreceptors and
subtypes.
·
Physiological
effects of endogenous catecholamines.
Synthesis, metabolism and excretion
1.
Source of endogenous catecholamines:
a.
Noradrenaline is released by most sympathetic neurons at their targets.
b.
Adrenaline is synthesized by neurons of the adrenal medulla and is
secreted directly into the bloodstream by sympathetic stimulation.
2.
Synthesis and storage of catecholamines:
a.
Most synthesis takes place at the storage sites such as the cytoplasm of
postganglionic sympathetic neurons, chromaffin cells of the adrenal medulla,
heart and arterioles, and specific areas of the CNS.
b.
In the granules of nerve terminals noradrenaline is held in two
functional pools, a labile pool from which it is liberated by nerve stimulation,
and a storage pool in equilibrium with the labile pool.
c.
The granular labile pool is in equilibrium with cytoplasmic pool which is
also labile.
d.
Tyramine and ephedrine acts to displace cytoplasmic labile pool while
reserpine will deplete both labile pools.
3.
Steps in synthesis of noradrenaline:
a.
The amino acid tyrosine is transported into the noradrenergic ending or
varicosity by a sodium-dependent carrier.
b.
Tyrosine is converted to the dopa by tyrosine hydroxylase.
c.
Dopa is converted to dopamine which is transported into a vesicle
containing dopamine-b-hydroxylase by a carrier.
d.
Dopamine is converted into norepinephrine by dopamine-b-hydroxylase and is stored in the granule.
4.
Release:
a.
Release of transmitter occurs when an action potential opens
voltage-sensitive calcium channels and increase intracellular calcium.
b.
Fusion of vesicles with the surface membrane results in expulsion of
noradrenaline.
5.
Termination of action:
a.
Reuptake into adrenergic nerve endings: an active process inhibited by
cocaine, phenoxybenzamine and all antipsychotics and antidepressants.
b.
Metahydroxyl group methylated by COMT and both re-entry and activity
terminated.
c.
Diffuses out of the synaptic cleft into the bloodstream.
d.
Oxidative deamination by MAO.
e.
The main produce (after methylation and oxidation) is
3-methoxyl-4-hydroxyl-mandelic acid.
Adrenoceptor and Subtypes
|
Adrenoceptors |
Sensitivity |
Result of Ligand binding |
|
Alpha1 |
Epinephrine > Norepinephrine
>> isoproterenol |
Coupled to Phospholipase C Formation of IP3 and DAG Increased intracellular calcium |
|
Alpha2 |
Epinephrine > Norepinephrine >> isoproterenol |
Inhibition of adenylyl cyclase Decreased cAMP |
|
Beta1 |
Isoproterenol > Epinephrine >
Norepinephrine |
Stimulation of adenylyl cyclase Increased cAMP |
|
Beta2 |
Isoproterenol > Epinephrine >
Norepinephrine |
Stimulation of adenylyl cyclase Increased cAMP |
Physiological effects of catecholamines
|
Subtype |
Tissue |
Actions |
|
Alpha1 |
Most vascular smooth muscle |
Contraction |
|
Pupillary dilator muscle |
Contraction (dilates pupil) |
|
|
Pliomotor smooth muscle |
Erect hair |
|
|
Heart |
Increase force of contraction. |
|
|
|
Bladder sphincter |
Contraction. |
|
Uterus |
Contraction |
|
|
Alpha2 |
Postsynaptic CNS adrenoceptors |
Multiple. |
|
Presynaptic autoreceptors |
Mediate negative feedback which
inhibits noradrenaline release. |
|
|
Platelets |
Aggregation |
|
|
Adrenergic and cholinergic nerve
terminals |
Inhibition of transmitter release. |
|
|
Some vascular smooth muscle |
Contraction. |
|
|
Fat cells |
Inhibition of lipolysis. |
|
|
Beta1 |
Heart |
Increase force and rate of
contraction. |
|
Beta2 |
Respiratory, uterine, vascular, GIT
smooth muscle |
Relaxation. |
|
Skeletal muscle |
Promote potassium uptake, leading to
hypokalaemia. |
|
|
Uterus |
Relaxation. |
|
|
Bladder detrusor |
Relaxation. |
|
|
Human liver |
Activate glycogenolysis. Activates lipolysis. |