Learn the nor adrenergic transmission in ANS. Synthesis, storage ,release, uptake,metabolism of nor-adrenaline. Types of adrenoceptors. Agonist and antagonist of adrenoceptors.

1. NORADRENERGIC
TRANSMISSION
NEUROHUMORAL
TRANSMISSION IN ANS
- By Lalita shahgond
B.pharm
SSR COLLEGE OF
PHARMACY , SILVASSA

2. The transmission of impulse
through synapse and neuro-effector
junction by the release of humoral
(chemical) substances…
What is neurohumoral transmission

3. CATECHOLAMIN
ES
 Catecholamine's are compounds containing a catechol
moiety (a benzene ring with two adjacent hydroxyl
groups) and an amine side chain
 the most important ones are:
• noradrenaline (norepinephrine), a transmitter
released by sympathetic nerve terminals
• adrenaline (epinephrine), a hormone
secreted by the adrenal medulla
• dopamine, the metabolic precursor of nor
adrenaline and adrenaline, also a
transmitter/neuromodulator in the central nervous
system
• isoprenaline (isoproterenol), a synthetic
derivative of nor adrenaline, not present in the

4. PHYSIOLOGY OF
NORADRENERGIC
TRANSMISSION
 The noradrenergic neuron:
Noradrenergic neurons in the periphery
are postganglionic sympathetic neurons
whose cell bodies are situated in
sympathetic ganglia.

5. - they generally have long axons that end in
the series of varicosities strung along the
branching terminal network
These varicosities contain numerous
synaptic vesicles, which are the sites
of synthesis and release of nor
adrenaline and of co-released
mediators such as ATP and
neuropeptide Y which are stored in
vesicles and released by exocytosis.

6. NORADRENALINE SYNTHESIS
 The metabolic precursor for noradrenaline
is L-tyrosine, an aromatic amino acid that
is present in the body fluids and is taken
up by adrenergic neurons.
 Tyrosine hydroxylase, a cytosolic enzyme
that catalyses the conversion of tyrosine to
dihydroxyphenylalanine (dopa).
 This above hydroxylation step is the main
control point for noradrenaline synthesis (rate
limiting step).
 Tyrosine hydroxylase is inhibited by the
end product of the biosynthetic pathway,
noradrenaline.

7. The biosynthetic pathway for nor
adrenaline synthesis

8. • The tyrosine analogue α-methyltyrosine strongly
inhibits tyrosine hydroxylase and has been used
experimentally to block nor adrenaline synthesis.
• The next step, conversion of dopa to
dopamine, is catalyzed by dopa decarboxylase, a
cytosolic enzyme that is by no means confined
to catecholamine-synthesising cells.
• Dopa decarboxylase activity is not rate-limiting
for noradrenaline synthesis
• It is a relatively non-specific enzyme, and
catalyses the decarboxylation of various other L-
aromatic amino acids, such as L-histidine and L-
tryptophan, which are precursors in the synthesis
of histamine.

9. • Dopamine-β-hydroxylase (DBH) is also a
relatively nonspecific enzyme, that catalyses the
conversion of dopamine to noradrenaline.
• Many drugs inhibit DBH, including copper-
chelating agents and disulfiram (a drug used
mainly for its effect on ethanol metabolism.
• Phenylethanolamine N-methyl transferase
(PNMT) catalyses the N-methylation of nor
adrenaline to adrenaline. The main location
of this enzyme is in the adrenal medulla.

10. NORADRENALINE
STORAGE• Most of the nor adrenaline is stored in
nerve terminals or chromaffin cells is
contained in synaptic vesicles; only a little is
free in the cytoplasm under normal
circumstances.
• The concentration in the vesicles is very
high (0.3–1.0 mol/l) and is maintained by
the vesicular monoamine transporter (VMAT),
which is similar to the amine transporter
responsible for nor adrenaline uptake into the
nerve terminal.• The vesicles contain two major constituents
besides nor adrenaline, namely ATP (about four
molecules per molecule of nor adrenaline). This
substance is released along with nor
adrenaline.

11. NORADRENALINE RELEASE
• 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 nor adrenaline from
vesicles.
• Noradrenaline escapes via the NET transporter
(reverse transport).
• Transmitter action is terminated mainly by
reuptake of nor adrenaline into nerve terminals via
• Nor adrenaline with ATP are released by exocytosis.

12. • NET is blocked by tricyclic antidepressant
drugs and cocaine.
• Noradrenaline release is controlled by
autoinhibitory feedback mediated by α2 receptors.
• Co-transmission occurs at many noradrenergic
nerve terminals, ATP and neuropeptide Y being
frequently co-released with NA.
• ATP mediates the early phase of smooth
muscle contraction in response to sympathetic
nerve activity.
• Noradrenaline, by acting on presynaptic β2
receptors, can regulate its own release, and also
that of co-released ATP.

13. Feedback control of noradrenaline (NA) release.
The
presynaptic
α2 receptor
inhibits Ca+2
influx in
response to
membrane
depolarisation
via an
action of the
βγ subunits
of the
associated G
protein on
the voltage-
dependent

14. • The depolarization of the nerve terminal causes activation of
the calcium channel.
• The calcium channel opens and ca+2 ion enters into the
cell, the calcium ions influx causes depolarization inside the
cell.
• Depolarization leads to exocytosic release of nor
adrenaline with ATP from the vesicle.
• Released NA bind to the postsynaptic receptors and
produce respective effects.
• NA bind to the α2 adrenoceptor which is auto receptor it
inhibits the NA release.

15. • Gi / Go that are the α subunit of GPCR they are
responsible for 3 activities :-
- Gi regulates the opening of potassium channel and
the inhibition of adenyl cyclase.
- Go regulates the opening of the calcium channel.
-The potassium channel opens and the K+ ions move
outside the cell this causes repolarisation of the cell. This
inhibits exocytosis of NA
- The inhibition of the adenyl cyclase inhibits the
conversion of ATP to C AMP this inhibits the opening of
calcium channel. This inhibits exocytosis of NA.

16. UPTAKE AND DEGRADATION OF
CATECHOLAMINES (nor adrenaline)
The action of released nor adrenaline is
terminated mainly by reuptake of the
transmitter into noradrenergic nerve terminals.
Circulating adrenaline and noradrenalin are
degraded enzymically, but much more slowly than
acetylcholine.

17. UPTAKE OF
CATECHOLAMINESAbout 75% of the nor adrenaline released by
sympathetic neurons is recaptured and
repackaged into vesicles.
This serves to cut short the action of the
released nor adrenaline, as well as recycling it.
The remaining 25% is captured by non-neuronal
cells in the vicinity, limiting its local spread.
These two uptake mechanisms depend on
distinct transporter molecules.
Neuronal uptake is performed by the plasma
membrane nor adrenaline transporter (generally
known as NET, the nor epinephrine transporter),
which belongs to the family of neurotransmitter

18. THE UPTAKE OF NOR ADRENALINE IS
OF 3 TYPES :-
1. AXONAL UPTAKE
2. VESICULAR UPTAKE
3. EXTRANEURONAL UPTAKE

19. AXONAL UPTAKE
 An active amine pump (NET) is present at the neuronal
membrane which transports NA by a Na+ coupled
mechanism.
 It takes up NA at a higher rate than Adrenaline and had
been labelled uptake-1.
 The indirectly acting sympathomimetic amines like
tyramine, but not isoprenaline, also utilize this pump for
entering the neurone.
 This uptake is the most important mechanism for
terminating the postjunctional action of NA.
 From 75% to 90% of released NA is retaken back into
the neurone.
 This pump is inhibited by cocaine, desipramine and few

20. VESICULAR UPTAKE
 The membrane of intracellular vesicles has another
amine pump the ‘vesicular monoamine transporter’
(VMAT-2), which transports NA from the cytoplasm to
the interior of the storage vesicle.
 The VMAT-2 transports monoamines by exchanging
with H+ ions.
 The vesicular NA is constantly leaking out into the
axoplasm and is recaptured by this mechanism.
 This carrier also takes up DA formed in the axoplasm
for further synthesis to NA.
 Thus, it is very important in maintaining the NA content
of the neurone.
 This uptake is inhibited by reserpine, resulting in

21. Extraneuronal uptake
 Extraneuronal uptake of CAs (uptake-2) is carried
out by extraneuronal amine transporter (ENT or
OCT3) and other organic cation transporters
OCT1 and OCT2 into cells of other tissues.
 In contrast to NET this uptake transports
Adrenaline at a higher rate than NA, is not Na+
dependent and is not inhibited by cocaine, but
inhibited by corticosterone.
 It may capture circulating Adr, but is quantitatively
minor and not of physiological or pharmacological
importance.

22. METABOLIC DEGRADATION OF
CATECHOLAMINES (NOR
ADRENALINE)
- Endogenous and exogenous catecholamines are
metabolised mainly by two intracellular
enzymes:-
- Monoamine oxidase (MAO)
- Catechol-O-methyl transferase (COMT).
- MAO (of which there are two distinct
isoforms) MAO-A and MAO-B is bound to
the surface membrane of mitochondria.
- It is abundant in noradrenergic nerve
terminals but is also present in liver,
intestinal epithelium and other tissues.
- MAO converts catecholamines to their
corresponding aldehydes, which in the
periphery, are rapidly metabolised by
aldehyde dehydrogenase to the corresponding
carboxylic acid.

24. • NA Converted to NM by COMT
• MAO catalyses conversion of NM to NM aldehyde
• NM aldehyde is directly converted to VMA by ADH, VMA is
the major metabolite which is excreted through urine.
• when MAO enzyme acts on the NA it gets converted to NA
aldehyde
• AR converts the NM aldehyde directly into the MHPG, which
is a minor metabolite of NA and it is excreted through urine.
• ADH converts NA aldehyde to DHMA further the DHMA is
converted to VMA by COMT
• AR catalyses the conversion of NA aldehyde to DHPG which
is catalysed to MHPG by COMT.

26. The catecholamine's should
bind to the adrenoceptors to
produce effects…
ADRENOCEPTORS

27. CLASSIFICATION OF ADRENOCEPTORS
α β
α1 α2 β1 β2
β3
А В Ϲ А В Ϲ
α: nor adrenaline > adrenaline > isoprenaline

28. Classification of adrenoceptors
• Main pharmacological classification into α
and β subtypes, based originally on order
of potency among agonists, later on
selective antagonists.
• Adrenoceptor subtypes: – two main α-
adrenoceptor subtypes, α1 and α2, each
divided into three further subtypes (1-/2-
A,B,C)
– three β-adrenoceptor
subtypes (β1, β2, β3)
– all belong to the super
family of G protein-coupled receptors.

29. • Second messengers:
– α1 receptors activate phospholipase
C, producing inositol trisphosphate and
diacylglycerol as second messengers
– α2 receptors inhibit adenylyl cyclase,
decreasing cAMP formation
– all types of β receptor stimulate
adenylyl cyclase

30. •. • The main effects of receptor activation are as
follows:
– α1 receptors: vasoconstriction, relaxation of
gastrointestinal smooth muscle, salivary secretion
and hepatic glycogenolysis
– α2 receptors: inhibition of: transmitter release
(including nor adrenaline and acetylcholine release
from autonomic nerves); platelet aggregation;
vascular smooth muscle contraction; insulin release
– β1 receptors: increased cardiac rate and
force
– β2 receptors: bronchodilatation; vasodilatation;
relaxation of visceral smooth muscle; hepatic
glycogenolysis; muscle tremor
– β3 receptors: lipolysis and thermogenesis;
bladder detrusor muscle relaxation.

33. ADRENOCEPTOR AGONISTS
• Selective α1 agonists include phenylephrine and
oxymetazoline.
• Selective α2 agonists include clonidine and α-
methylnoradrenaline. They cause a fall in blood
pressure, partly by inhibition of nor adrenaline
release and partly by a central action.
• Selective β1 agonists include dobutamine.
Increased cardiac contractility may be useful
clinically, but all β1 agonists can cause cardiac
dysrhythmias.
• Selective β2 agonists include salbutamol,
terbutaline and salmeterol; used mainly for their
bronchodilator action in asthma.
• A selective β3 agonist, mirabegron, is used to
treat overactive bladder; β3 agonists promote
lipolysis and have potential in the treatment of