Transcript Parasympathetic NS I

Pharmacology-1 PHL 351
Abdelkader Ashour, Ph.D.
Parasympathetic Nervous
System
Some anatomic and neurotransmitter features of
autonomic and somatic motor nerves
N.B. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated
Summary of parasympathetic neurons
and synapses
Preganglionic neurons
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Long
Synapse with postganglionic neurons at or near organ
Release acetylcholine (Ach) to activate nicotinic receptors on postganglionic
neurons
Postganglionic neurons
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Short
Synapse on the target organ
Release ACh to activate muscarinic receptors on the target organ
Cholinergic fibers: i.e., act by releasing acetylcholine.
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Include:
– all preganglionic efferent autonomic fibers
– the somatic (non-autonomic) motor fibers to skeletal muscle
– most parasympathetic postganglionic and a few sympathetic postganglionic
fibers
Cholinergic
Transmission
 The terminals of cholinergic
neurons contain large
numbers of small
membrane-bound vesicles
(containing ACh)
concentrated near the
synaptic portion of the cell
membrane.
 ACh is synthesized in the
cytoplasm from acetyl-CoA
and choline through the
catalytic action of the
enzyme choline
acetyltransferase (ChAT).
 Acetyl-CoA is synthesized in
mitochondria, which are
present in large numbers in
the nerve ending.
Cholinergic
Transmission
Choline is transported from the
extracellular fluid into the neuron
terminal by a sodium-dependent
membrane carrier (carrier A). This
carrier can be blocked by a group of
drugs called hemicholiniums.
The action of the choline
transporter is the rate-limiting step
in ACh synthesis.
Once synthesized, ACh is transported
from the cytoplasm into the vesicles by
an antiporter that removes protons
(carrier B). This transporter can be
blocked by vesamicol.
Storage of ACh is accomplished by
the packaging of "quanta" of ACh
molecules (usually 1000–50,000
molecules in each vesicle).
Cholinergic
Transmission
Release of ACh is dependent on extracellular
calcium and occurs when an action potential
reaches the terminal and triggers sufficient
influx of calcium ions.
The increased Ca2+ concentration
"destabilizes" the storage vesicles by
interacting with special proteins associated with
the vesicular membrane.
Fusion of the vesicular membranes with the
terminal membrane occurs through the
interaction of vesicular proteins (vesicleassociated membrane proteins, VAMPs), eg,
synaptotagmin and synaptobrevin with several
proteins of the terminal membrane
(synaptosome-associated proteins, SNAPs),
eg, SNAP-25 and syntaxin.
Fusion of the membranes results in exocytotic
expulsion of ACh into the synaptic cleft.
The ACh vesicle release process is blocked
by botulinum toxin through the enzymatic
removal of two amino acids from one or more of
the fusion proteins.
Cholinergic
Transmission
After release from the presynaptic
terminal, ACh molecules may bind to and
activate an ACh receptor (cholinoceptor).
Eventually (and usually very rapidly), all of
the ACh released will diffuse within range of
an acetylcholinesterase (AChE) molecule.
AChE very efficiently splits ACh into
choline and acetate, neither of which has
significant transmitter effect, and thereby
terminates the action of the transmitter.
Most cholinergic synapses are richly
supplied with AChE; the half-life of ACh in
the synapse is therefore very short. AChE is
also found in other tissues, eg, red blood
cells.
Another cholinesterase with a lower
specificity for ACh, butyrylcholinesterase
[pseudocholinesterase], is found in blood
plasma, liver, glia, and many other tissues
Parasympathetic Nervous System,
Receptors for acetylcholine (cholinoceptors)
I.
Nicotinic receptors, nAChRs (the nicotinic actions of ACh are those that can
be reproduced by the injection of nicotine) ---- Nicotinic receptors are ligandgated ion channels whose activation results in a rapid increase in cellular
permeability to sodium and calcium.
1.
At neuromuscular junctions of skeletal muscle (muscle type)
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2.
Postsynaptic
Excitatory (increases Na+ permeability)
Agonists: ACh, carbachol (CCh), suxamethonium
Stimulate skeletal muscle (contraction)
Antagonists: tubocurarine, hexamethonium
On postganglionic neurons in the autonomic ganglia (ganglion type)
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Postsynaptic
Excitatory (increases Na+ permeability)
Agonists: Ach, CCh, nicotine
Stimulate all autonomic ganglia
Antagonists: mecamylamine, trimetaphan
Parasympathetic Nervous System,
Receptors for acetylcholine
3.
On some central nervous system neurons (CNS type)
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4.
Pre- and postsynaptic
Excitatory (increases Na+ permeability)
Agonists: nicotine, ACh
Pre- and postsynaptic stimulation of many brain regions
Antagonists: methylaconitine, mecamylamine
On adrenal medulla
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Ach stimulates secretion of adrenaline from adrenal medulla
Parasympathetic Nervous System,
Receptors for acetylcholine
II.
Muscarinic receptors, mAChRs (the muscarinic actions of ACh are those
that can be reproduced by the injection of muscarine) ---- Muscarinic receptors
are GPCR: (odd-numbered members “M1, M3, M5) act through the inositol
phosphate pathway, while the even-numbered receptors (M2, M4) act by inhibting
adenylate cyclase, and thus reducing intracellular cAMP. mAChR also may
activate or inhibit potassium channels and calcium channels.
Location: mAChRs are located …
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in tissues innervated by postganglionic parasympathetic neurons such as
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On smooth muscle
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On cardiac muscle
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On gland cells
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See next table for details. For more information, see also Table 9.1, p127,
RDRM
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in postganglionic sympathetic neurons to sweat glands
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In the central nervous system
G-protein-Coupled Receptors, targets
Main locations
Cellular response
Functional
response
Agonists
Antagonists
P139
RDRM
Demonstration of Muscarinic and Nicotinic Actions of ACh
A.
B.
C.
D.
Two kinds of effects produced by Ach.
Ach causes a fall in BP due to vasodilation
A larger dose of Ach also produces bradycardia, further reducing BP.
Atropine blocks the effect of Ach in lowering BP.
Still under the influence of atropine, a much larger dose of Ach produces nicotinic
effects, causing a rise in BP and tachycardia due to stimulation of sympathetic
ganglia and secretion of adrenaline.
Muscarinic Autonomic Effects of Acetylcholine
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Eye (iris sphincter muscle)
Eye (ciliary muscle)
SA node
Atrium
AV node
Arteriole
Bronchial muscle
Bronchial secretion
GIT (motility)
GIT (secretion)
GIT (sphincters)
Gallbladder
Urinary bladder (detrusor)
Urinary bladder (trigone, sphincter)
Penis
Sweat glands
Salivary glands
Lacrimal glands
Nasopharyngeal glands
Contraction (miosis)
Contraction (for near vision)
Bradycardia
Reduced contractility
Reduced conduction velocity
Dilation (via nitric oxide)
Muscle Contraction
Increase
Increase
Increase
Relaxation
Contraction
Contraction
Relaxation
Erection (but not ejaculation)
Secretion (sympathetic cholinergic!)
Secretion
Secretion
Secretion