We talked in the previous lecture that Acetylcholine is hydrolyzed by

acetylcholine esterase and that contaminate the action of acetyl choline.

Catecholamine is terminated by uptake into the nerve terminal and
storage. This occurs in two steps:
1- from synapse to the axoplasm
2- from axplasm into the synaptic vesicle

Note: Certain drugs affect these processes and are important in

therapeutics.

From synapse to the axoplasm:

We have 2 classes of drugs acting on this transport mechanism: Cocaine
and Tricyclic antidepressant.
* Cocaine (a drug of abuse) inhibits this reuptake mechanism. Cocaine
increases the levels of catecholamine at the synapse
-Catecholamines –In general- in CNS can be stimulated. Cocaine is a
stimulating agent –so causing addiction-.
*Also Tricyclic antidepressant drugs increase the level of catecholamine
in synapse by inhibiting the uptake mechanism.
From axoplasm into the synaptic vesicle:
It is inhibited by 2 classes of antihypertensive agents: Reserpine and
Bretylium guanithidine.
*Reserpine is a drug used to treat hypertension and acts by inhibiting
reuptake or transform into the synaptic vesicle.
-When you prevent the storage in the synaptic vesicle Æ it goes under
depletion (the amount of catecholamines in the synaptic vesicle is small)
so if nerve stimulation occurs, the amount of catecholamines leaving the
vesicle is small Æ so we will have normal blood pressure.
-Note: Blood pressure depends on: catecholamine, cardiac output and
peripheral vascular system.
* Bretylium guanithidine: these agents inhibit the release of
catecholamines. So it participates in reducing blood pressure.

*Catecholamine scheme is more complicated and controlled than

Acetylcholine one.
In acetylcholine scheme, there are factors can be used to inhibit certain
processes but they are not important therapeutically. But they are
important therapeutically in catecholamine.

* What will happen if catecholamines diffused from the vesicle to the

axoplasm and catecholamines can't return back to the synapse?
Catecholamines will be metabolized by mitochondrial enzymes.
-However if catecholamines are secreted to the blood, they will go with
the blood flow to the liver and then metabolized there.
Catecholamine synthesis:

Notes:
’ Dopa: Dihydroxyphenyl alanine.
’ Types of catecholamine: Dopamine, Norepinephrine and
Epinephrine.
’ Dopamine doesn't contain a hydroxyl group on C (take a look at the
figure).
’ Norepinephrine contains a hydroxyl group on C. This hydroxyl group
(which is found in norepinephrine but not in dopamine) makes many
differences between norepinephrine and dopamine: different
receptors, actions and locations.
’ If we methylate the amine group in norepinephrine (nor methyl) we
will have epinephrine. This methyl group makes the Epinephrine
more selective to the β-receptors than norepinephrine. (More bulk
Æmore selective for β-receptors).

Tyramine: (in the same figure)

- A monoamine compound derived from the amino acid tyrosine by L-
amino acid decarboxylase.
- It is taken up by the same transport mechanisms for
catecholamines and get stored in the vesicles.
- It displaces catecholamine.
- At the beginning, tyramine released into the vesicles in large
numbers causing hypertensive crises (due to the large amount).
- Synthesized in the body but in small amounts. Found also in: cheese
(especially stored cheese) and wine. If the person eats too much
 cheese and drinks a lot of wine, s/he will suffer from high blood
pressure if the metabolism of tyrosine is inhibited.
- Tyramine is metabolized by monoamine oxidase (MAO), the same
that metabolize catecholamine.
- You inhibit MAO by MAO inhibitor (ex: antidepressant drugs). So
if someone is taken an antidepressant drug (MAO inhibitor), he
mustn’t eat cheese or drink wine, otherwise he will suffer from
hypertension crises.

Catecholamine:
™ Structure: catechol + amine
™ Catechol: benzene ring with 2 hydroxyl groups in Ortho and
Meta positions. We call this structure in organic chemistry
chatecol nucleus.
™ Inhibited by 2 enzymes:
1-MAO (monoamine oxidase): it links to catecholamine by
o- monoamine oxidase. It is a mitochondrial enzyme in the liver
and nervous tissue. It oxidizes the amine group and the carbon
next to it.
2-COMT (catechol-o-methyltransferase): -conjugate to
catecholamine mainly in the liver and other tissues.
Notes:
 It doesn’t matter which one (MAO, COMT) acts first we will have
the same end result.
 whatever the enzymes acts first or if you are talking about
epinephrine or norepinephrine, the final product is Vanil Mandelic
Acid (VMA or 3-methoxy-4-hydroxy-mandelic acid)
 VMA: if we have excessive sympathetic stimulation and we expect
that the concentration of epinephrine or norepinephrine is high
(hard to measure) and we found that VMA is highÆ we know that
the concentration of epinephrine, norepinephrine or both of them
is high.
 Tumors in sympathetic chain (ex: phyochromocytoma) secretes
tremendous amounts of catecholamine.
If the patient comes to your clinic and told you that he is suffering
from rapid hypertension for a short while then his pressure returns to
the normal. You realize that the problem is: phyochromocytoma.
The same problem happens also in some patients in fear, fight and
flight Æ suddenly increasing in the hypertensionÆblood pressure id
high (presence of catecholamine). So you –as a DR- ask him to bring a
urine sample, and then check the VMA concentration.

Dopamine:
-metabolized by MAO and COMT also
-The end product is Homovanillic acid
-if there is an increase of the homovallinic acid in the urine, this
leads to an increase concentration of dopamine.

Autonomic Receptors:

-Adrenoreceptors contain also epinephrine.

Notes:
-These are receptors of all of the body (We will focus on A.N.S)
-These receptors are: muscarinic and nicotinic, in peripheral nervous
system and C.N.S
-In peripheral N.S you have cholinergic receptors in A.N.S and in motor
nervous system.
-Muscarinic receptors consist of 5 subtypes (M1-M5). They are not
identical
-Nicotinic receptors consist of 2 subtypes (Nn, Nm)
-M1 receptor: *sympathetic postganglionic neuron: in sweat glands
*subpresynaptic site: for regulation in autoreceptor (acting
On the same neuron) or heteroreceptor (activated by
Substances released from other nerve terminal)
-M2 receptor: smooth muscle found in: blood vessels, GI tract and urinary
tract.
-M5: cerebral vessels: brain blood vessels.
-Nn: nicotinic nervous system
-Nm: nicotinic muscular system
Adrenoreceptors:

™ Subtypes of adrenergic receptors are: ɑ1, ɑ2, β1, β2 and β3.

™ ɑ1 : smooth muscles in GI tract, urinary tract and blood vessels
™ ɑ2: mainly presynaptic adrenergic nerve terminals. It is responsible
for inhibition (regulation). Autoreceptors. Small amount in smooth
muscles.
™ β1: found in renal tubules. It is responsible for rennin secretion in
renal tubules, in addition to β1 in the heart. Postsynaptic
adrenergic nerve terminal contain B1 receptor which function is
regulation (stimulation for catecholamine, positive and negative
feedback)
™ Β2: found in the heart. But mainly we have B1 more than B2 in the
heart.
-in vessels we have mainly a1 and B2.
-a1 in the vessel is stimulatory (vasoconstriction)
-B2 in the vessel is inhibitory (vasodilation)
-so a1 and B2 have different functions in the vessel.
™ B3: found mainly in lipocytes.
-Maybe Drugs that modify B3 receptors are useful in treating
obesity. (Not sure till now)
 Dopamine Receptors:
-dopamine is central neurotransmitter

**D1 receptors:
• Found mainly in the brain.
• Present in renal vascular bed.
• Responsible for vasodilation in renal blood vessels to protect
the kidney from ischemia (kidney weight= 5/1000 of total
body weight, but it receives 25/100 of the cardiac output) if
there is ischemia in the kidney and D1 receptors are
deactivated, kidney will go under necrosis. So D1 receptors
are protective system for the kidney.

Presynaptic Regulation:
 - B-adrenoceptors are B1
- If the Norepinephrine is low in the body, B1 receptors will be
stimulated.
- If the Norepinephrine is high in the body, a2 receptors will be
stimulated.

-Vagal fibres from vagus nerve.

-Note 1 (some vagal fibres….): adrenergic nerve terminals
(sympathetic) and presynaptic cholinergic receptors stimulated by
acetylcholine. Once the vagal fibres are stimulated, inhibition of the
release of Norepinephrine will occur.
-Note 2 (alternatively…): it isn’t necessary to have nerve terminals.
Maybe the acetylcholine or any similar substances coming in the blood
stream interact with the receptors and stimulate it (inhibition of
catecholamine release).
-Serotonin: 5-hydroxytryptamine
-P1 and P2: purine receptors for ATP and adenosine
-Angiotensin 2: -Stimulate adrenergic nerve terminals Æ
vasoconstrictionÆincrease blood flow.
-Stimulate Aldosterone: reabsorption of Na+ and waterÆ
increase in blood volumeÆincrease cardiac outputÆblood pressure.

Postsynaptic Regulation:

-Up-regulation: synthesis
-Down regulation: blocking of the receptors
-If you have excessive stimulation of Alpha receptors Æ down regulation
occurs to achieve the balance.
-When there is blocking of Alpha receptors Æ Up-regulation occurs to
achieve the balance.
-Down regulation and Up-regulation happen in seconds to days.
-In seconds: endocytosis (down regulation because of excessive
stimulation)
-In days: when there is protein synthesis (stimulation or inhibition)
*You have to memorize these actions.
In The Eye:
: Myoses: constriction of pupil.
: Medriosis: dilation of pupil.
: Iris has 2 muscles: circular and radial

:
: If the circular muscle is stimulated Æ constriction (myoses)
: If the radial muscle is stimulatedÆ dilation (medriosis)
: Ciliary muscle is stimulated by B-adrenergic receptors and M3
cholinergic receptors.
 -M3 receptors contract the ciliary muscle to accommodate for near
vision. (Accommodate: focus and adapt your eye for near vision)
- B-receptors relax the ciliary muscle of eye for far vision.

In The Heart:
’ S.A node: pacemaker.
’ We have B1 and B2 sympathetic receptors. B1 are more in No. than
B2.
’ B1 are also more important than B2. Æ Acceleration to the heart
and any ectopic pace maker. They also increase the contractility of
the heart
’ Parasympathetic activity receptors (M2 receptors) Æ decelerate
the heart. M2 receptors also decrease the contractility of the
heart especially in the atrium.

In blood vessels:
-What is the M3 sympathetic receptor??!!!
Answer: certain neurons in sympathetic nervous system use acetylcholine.
These neurons are called sympathetic cholinergic receptors. We have this
type of receptors in: 1-sweat glands 2-some blood vessels.
-Cholinergic system (M3, M5) relax smooth muscles of certain blood
vessels indirectly. The receptors stimulate the endothelium to secrete
EDRF (endothelium derived relaxing factor) which will relax the smooth
blood vessels. (Two steps: 1- cholinergic receptors in endothelial cells
secrete EDRF. 2- EDRF inhibit (relax) the smooth muscles in blood
vessels)
-EDRF: nitric oxide.

In Bronchiolar Smooth Muscles:

 In sympathetic: GI tract will be relaxed by a2 and B2 receptors
and sphincter contracted Æ keep contents in.
 In parasympathetic: wall contracted and sphincter relaxed Æ
evacuation, defection and urination. Secretions are increased also
by M3 stimulation all over the body. (GI, lacrimal and salivary
secretions)
 The pregnant uterus is relaxed by B2 receptors. So doctors must
give B2 receptors to the pregnant woman who is going to deliver
her baby before the expected date of delivery to relax the
uterus. But non-pregnant woman won't be affected by both
sympathetic and parasympathetic.
Note: sex organs when stimulated by sympathetic receptors Æ
ejaculation.

Effects Of Autonomic Nerve Activation:

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