AUTONOMICS (part2)

Lecture by Dr. Valerio

Let us again review this diagram. This is the efferent pathway of the somatic nervous system and the
different divisions of the autonomic nervous system.

Somatic NS - one-neuron efferent fiber. From the center, a somatic efferent nerve will form a synapse
with the membrane of the skeletal muscle cell which is the effector cell. This area is called the neuro-
muscular junction - where transmission of motor impulses will take place from a somatic efferent nerve
ending to the skeletal muscle cell membrane.

Parasympathetic efferent pathway - two-neuron efferent nerve. From the center, the pre-ganglionic
fiber will first synapse with the peripheral ganglion. And then you have the post-ganglionic fiber forming
a synapse with the membrane of the effector cell and this area is the neuro-effector junction. And the
effector cells here are the cardiac muscle cell, visceral smooth muscle cell and glands.

Biochemically we divided the sympathetic into two Sympa Cholinergic and Sympa Adrenergic NS.
They have the same structure. They have a two-neuron efferent nerve.
SympaCholi effector cells: sweat glands, vascular smooth muscle cells present in the skeletal muscle.
SympaAdre effector cells: cardiac muscle cell, visceral smooth muscle cell, glands.

Cholinergic transmission
- mediated by Acetylcholine
- present in ALL:
Somatic NMJ (that means that it is Ach that will mediate transmission of motor impulses
from all somatic efferent nerves to the skeletal muscle cell).
Peripheral ganglia (means that transmission of impulses from all pre-ganglionic to all
post-ganglionic, both sympa and para, is mediated by Ach).

Transcribed by: BERNABE, M.K. (Dec 2012) Page 1

 Parasympa NEJ (means all parasympathetic effects to the different effector organs are
mediated by Ach)
* Since parasympathetic nerves release only one type of NTA that is Ach, when we say
cholinergic division, we refer to the Parasympa NS.
*PARASYMPA NS is known as craniosacral division (anatomically) and cholinergic
division (biochemically)
SympaCholi NEJ (means that sympathetic effects to sweat glands and blood vessels
present in the skeletal muscle are mediated by Ach)

Adrenergic transmission
- mediated by Norepinephrine
- present in ALL:
Sympa-Adre NEJ (means most of the sympathetic effects to the different effector organs
are mediated by Norepinephrine)
*When we say adrenergic division, we refer to the Sympa NS
*SYMPA NS is known as thoracolumbar division (anatomically) and adrenergic
division (biochemically)

Steps in Cholinergic Transmission:

1. Synthesis of Ach
- Ach is synthesized from Choline and Acetyl co-enzyme A. And this reaction is catalyzed by
the enzyme Choline Acetyl transferase.
2. Release of Ach by exocytosis into the synaptic cleft facilitated by Ca ions
- Ach will be stored temporarily in vesicles that are located in the axon terminal or nerve
ending. So that when an action potential reaches the nerve terminal, there will be Ca influx
that will facilitate the release by exocytosis of Ach to the synaptic cleft.
3. Ach binding to specific receptors
- Ach will now bind with specific receptors on the membrane of the effector cell that will elicit
a physiologic response from the effector cell.
- These receptors known as Cholonergic receptors. Two types:
i. Nicotinic receptors
Present in ALL: somatic NMJ (membrane of skeletal muscle cells),
autonomic/peripheral ganglion
ii. Muscarinic receptors
Present in ALL: para NEJ, sympa-choli NEJ
Diff. visceral organs and glands
Types:
M1 (muscarinic-1 receptors) mainly in brain, some in stomach
M2 most abundant; in the heart; also in visceral smooth muscles
M3 visceral smooth muscles and glands
M4 - visceral smooth muscles and glands
M5 least abundant; present ONLY in specific locations which will
include: sphincter muscle of the iris, esophagus, parotid gland and
cerebral blood vessels

Transcribed by: BERNABE, M.K. (Dec 2012) Page 2

Difference between Nicotinic and Muscarinic Receptors
NICOTINIC
Protein; Ligand-gated Ca channels
When Ach binds with nicotinic receptors open
up ligand gated Na channels Na influx
depolarize the membrane of the effector cell
excitatory response
RESPONSE: Excitatory
MUSCARINIC
g-protein coupled receptors
When Ach binds with a muscarinic receptor
activation of g-proteins activate intracellular
enzyme systems formation of a intracellular
ligand 2nd messenger will mediate the action
of Ach on the target cell allowing the target cell
to respond excitatory/inhibitory
RESPONSE: Excitatory/Inhibitory

-
4. After eliciting a response from the effector cell, Ach is rapidly deactivated by the enzyme
Acetylcholinesterase which is also present in the synaptic cleft. This will make
cholinergic/parasympa effects SHORT in duration.

Steps in Adrenergic Transmission:

1. Synthesis of Norepinephrine
- Norepinephrine is a catecholamine.
- It is synthesized by the amino acid Tyrosine.
- Biosynthesis:
i. Phenylalanine beta-tyrosine; catalyzed by Phenylalanine hydroxylase
ii. Beta-tyronsine Dopa; catalyzed by Tyrosine hydroxylase
iii. Dopa Dopamine; catalyzed by Dopa decarboxylase.
iv. Dopamine Norepinephrine; catalyzed by Dopamine beta-hydroxylase
- There is a negative-feedback control system that exists thus regulating the formation/
synthesis of Dopamine and Norepinephrine:
Excess Dopamine/Norepinephrine
Inhibit the enzyme Tyrosine hydroxylase
Tyrosine will not be converted to Dopa
Decrease Dopamine levels
Decrease Norepinephrine levels
- This reaction will take place in Sympathetic Adrenergic post-ganglionic nerve endings only.
- In the adrenal medulla
i. This reaction may also take place
ii. At the same time, Norepinephrine can be converted into another type of
cathecolamine and that is Epinephrine, catalyzed by the enzyme
phenylethinolamine n-metyl transferase.
- Conversion of NorEPi to EPI does NOT take place in sympa post ganglionic nerve endings,
but ONLY in the adrenal medulla.
2. Norepinephrine will be stored temporarily in vesicles located in the axon terminal or nerve
ending. Like Ach, when an action potential reaches the nerve terminal, there will be Ca influx
that will facilitate the release of Norepinephrine by exocytosis of Ach to the synaptic cleft. Upon
release, Norepinephrine, as well as circulating Epinephrine, will bind with specific receptors on

Transcribed by: BERNABE, M.K. (Dec 2012) Page 3

 the membrane of the effector cell. And there are 4 types of receptors that will bind to NorEPI
and Epi.and we call them adrenergic receptors:
a. Alpha-1 present in the visceral smooth muscle and glands
b. Alpha-2 present only on the nerve terminals
-have a negative-feedback effect. NorEPi will stimulate a-2 receptors. When
stimulated, a-2 receptors will inhibit further release of NorEPI.
c. Beta-1 present mainly in the heart
d. Beta-2 present n the visceral smooth muscle and glands

When alpha receptors are stimulated response of effector cell: mostly EXCITATORY
For example: When NorEPI binds with an a-1 receptor in the vascular smooth muscle, the vascular
smooth muscle will contract vasoconstriction (excitatory)

When NorEPI or EPI binds with a beta receptor response: mostly INHIBITORY.
For example: When NorEPI binds with an b-2 receptor in the bronchial smooth muscle, the bronchial
smooth muscle will relax and that will cause bronchodilatation.so that is inhibitory.

Exceptions:
I. Alpha receptors (in digestive system, bronchial glands and pancreatic islets)
Stimulated by NorEPI and EPI
Effect is inhibitory
DECREASE: GI motility and secretion
Bronchial gland secretion
Pancreatic islet secretion
II. NorEPI and EPI bind with beta receptors in the heart
Excitatory responses
INCREASE: heart rate
Force of myocardial contraction.

There are some sympathetic pre-ganglionic fibers that will synapse with the adrenal medullary
cells. When the Sympa NS is stimulated and pre-ganglionic fibers release Ach
This Ach will bind with nicotinic receptors present in the membrane of adrenal medullary
cells. Remember that adrenal medullary cells are histologically similar to a sympathetic ganglion.
Stimulated by Ach
Adrenal medullary cells will release two types of catecholamines: EPI and NorEPI.
80% of secretory product Epinephrine
20% - Norepinephrine
These two catecholamines are released into the circulating blood before they stimulate the
adrenergic receptors
Potentiating sympa adrenergic effects.
*****So the adrenal medulla is considered as part of the Sympa-Adrenergic NS.

All adrenergic receptors are g-protein coupled receptors. So when NorEPI or EPI will bind to a
adrenergic receptor, this will cause also activation of g-proteins as well as formation of a 2md
messenger or intracellular ligand.

Transcribed by: BERNABE, M.K. (Dec 2012) Page 4

Potency:
NorEPI can strongly stimulate alpha and beta-1 receptors. It weakly stimulates beta-2 receptors
EPI can strongly stimulate all adrenergic receptors (a-1, b-1, b-2); more potent than NorEPI

3. Deactivation of Norepinephrine
The main mechanism that will deactivate NorEPI is reuptake by the 3 junctional fibers,
destroyed secondarily by the enzyme Mono-Amine Oxidase.
For circulating EPI, it is transported to the liver, destroyed secondarily by the enzyme Catecho-o-
methyl transferase.

PHYSIOLOGIC/FUNCTIONAL DIFFERENCES

In almost all organs in the body, sympa and para are present.
When they are present in 1 organ, almost always they will exert OPPOSITE/antagonistic effects.
Conditions:
1. Dual innervation of the same structure in the same organ
Sympa and Para: Opposite/Antagonistic effect
Example: [Heart] Wherein the SA node (primary pacemaker of the heart), determines the
impulses generated in a normally functioning heart, determines the heart rate (no. of
beats/min). It is innervated by a sympa nerve and sympathetic stimulation si to increase the
heart rate. But at the same time it is innervated by the vagus nerve which is parasympathetic.
Parasympathetic stimulation decreases the heart rate. To maintain a normal HR, between 60-
100 beats/min, sympa and para are said to be in tone meaning they fire impulses
simultaneously balancing effect HR neither increases nor decreases; it is maintained at a
normal level.
2. Dual innervation of 2 different structures in the same organ
Sympa and Para: Opposite/Antagonistic effect
Example: [Iris] In the iris, there are two types of smooth muscles present: Radial muscle
(innervated by a sympathetic nerve) and Sphincter/Circular muscle (innervated by CN3 which is
parasympathetic). In the absence of light, Sympa stimulation predominates contraction of
the radial muscle of the iris increase pupillary size pupillary dilatation/MIDRIASIS.
In the presence of light, Para stimulation predominates contraction of the circular muscle of
the iris decrease pupillary size pupillary constriction/MYOSIS
3. Dual innervation of the same structure in the same organ
Sympa and Para: Synergistic effect
Example: [Salivary glands] Sympa stimulation causes a mild to moderate increase in salivary
secretion and the saliva produces is viscous. At the same time, parasympa stimulation will cause
a profuse increase in salivary secretion and the saliva produced is watery.
4. Single innervations
Kidneys, Vascular smooth muscle, pyro-erector muscle in the skin and sweat glands these
organs receive ONLY sympathetic innervations.

Transcribed by: BERNABE, M.K. (Dec 2012) Page 5

SYMPA: enable an individual to withstand stressful or emergency conditions/ fight-or-flight conditions
PARA: try to conserve or preserve the bodys processes; rest-or-digest response

SYMPA: Catabolic; there is much expenditure of energy

PARA: Anabolic

SYMPA: Prolonged in duration (bec. of circulating EPI and NorEPI from the adrenal medulla that will
reinforce sympa-adrenergic effects; Unlike Ach, NorEPi is not immediately deactivated by the enzyme
present in the synaptic cleft because the main mechanism that will deactivate NorEPI is reuptake by the
pre-junctional fiber)
PARA: Short in duration (mediated by Ach. Ach is rapidly deactivated by Acetylcholinesterase present in
the synaptic cleft.

Sympathetic effects that will enable a person to withstand stressful/emergency/ fight-or-flight

conditions:
Inc HR and BP (beta-1 receptors)
Peripheral vasoconstriction (alpha-1 receptors)
Inc Lipolysis (beta-2 receptors)
Coronary dilatation, Bronchodilation (beta-2 receptors)
Glycogenolysis (beta-2 receptors)

Parasympathetic effects that will conserve/restore the bodys processes (ParaSym effects are
mediated by Ach):
Dec in HR and BP (M-2 and M-3 receptors)
Peripheral vasodilatation (M-3 receptors)
Dec Lipolysis, Bronchoconstriction, Lipogenesis (M-3 receptors)

SYMPA: more diffused/widespread

Reasons: Extensive branching of pre-ganglionic fiber
Circulating EPI and NorEPi from adrenal medulla that will reinforce SymAdre effects
PARA: more localized (EXCEPT VAGUS NERVE) because of limited branching of pre-ganglionic fibers

SYMPA: reflexes are well-coordinated; always occur at the same time

PARA: While most reflexes are well-coordinated, there are some that do NOT occur at the same time:
erection, micturition and defecation

The ANS is involuntary. Its activities are NOT mediated by the cerebral cortex. Instead, the main
autonomic center is the Hypothalamus. But there are some autonomic activities that are mostly
involuntary, they can also be partly voluntary (partly controlled by cerebral cortex): respiration,
micturition, and defecation.

Hypothalamus (main center for autonomic activities)

Anterior mostly controls Cholinergic/PSNS activities
Postero-lateral control Adrenergic/SNS activities

Transcribed by: BERNABE, M.K. (Dec 2012) Page 6

PHARMACOLOGICAL DIFFERENCES

Cholinergic Drugs
Parasympathomimetic drugs
- Increase or potentiate parasympathetic/cholinergic effects
- Mechanism of action: Increase the synthesis of Ach
Increase the release of Ach
Promote the interaction between Ach and cholinergic receptors
Decrease the destruction/deactivation of Ach
E.g. Pyrocartine

Parasympatholytic drugs
- Decrease/inhibit/block cholinergic effects
- Mechanism of action: Decrease/inhibit synthesis of Ach
Block release of Ach
Block interaction between Ach and cholinergic receptors
Increase deactivation of Ach
E.g. Atropine

Adrenergic Drugs
Sympathomimetic drugs
- Increase or potentiate sympathetic/adrenergic effects
- Mechanism of action: Increase the synthesis of Norepinephrine
Increase the release of Norepinephrine
Increase interaction between NorEPI and adrenergic receptors
Decrease the deactivation of Norepinephrine
E.g. Adrenaline (Epinephrine)

Sympatholytic drugs
- Decrease/inhibit/block sympathetic effects
- Mechanism of action: Decrease/inhibit synthesis of Norepinephrine
Block release of Norepinephrine
Block interaction between Ach NorEPI and adre receptors s
Increase deactivation of Norepinephrine
E.g. Alpha-blockers, Beta-blockers

Transcribed by: BERNABE, M.K. (Dec 2012) Page 7