Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

THE PARASYMPATHETIC NERVOUS SYSTEM – CHOLINERGIC SYNAPSES
receptors on the vascular endothelium, which can
cause vasodilation by inducing production of the
endothelium-dependent relaxing factor nitric oxide
(NO), have no parasympathetic neuronal input. The
ciliary muscle of the eye and the smooth muscle of the
bronchi receive only parasympathetic innervation. Salivary
glands are innervated by sympathetic and parasympathetic
fibers but both deliver prosecretory stimuli.
The sympathetic nervous system has an important
role in tuning autonomic processes for the ‘fight-andflight’
state and the parasympathetic nervous system
contributes to the ‘rest-and-digest’ state. Under less
extreme physiological everyday conditions, however,
both systems jointly contribute to the maintenance of
homeostasis. This fact has been highlighted by the discovery
of a multitude of mechanisms that mediate
presynaptic and postsynaptic modulation of one system
by the other.
The most important biochemical distinction between
the two major parts of the autonomic nervous system
relates to the distribution of different neurotransmitters.
Generally, transmission from preganglionic to postganglionic
neurones is mediated by ACh acting on nicotinic
ACh receptors present in both sympathetic and parasympathetic
autonomic ganglia. Postganglionic transmission
at sympathetic target organ synapses is mediated
by noradrenaline (norepinephrine) acting on either α- or
β-adrenoceptors. In the parasympathetic nervous system,
on the other hand, postganglionic transmission occurs
via release of ACh which activates muscarinic ACh
receptors present on the postsynaptic membrane.
In addition to these two principal transmitters, a
variety of other substances are synthesized, stored and
may be released from autonomic nerve endings. These
so-called nonadrenergic and noncholinergic (NANC)
transmitters are summarized in Table 4.1. From a pharmacological
perspective this knowledge of other mediators
is only just starting to have an impact on clinical
applications (e.g. potential use of 5-HT, substance P and
VIP antagonists as antidiarrhea agents).
NEUROTRANSMISSION IN THE
AUTONOMIC NERVOUS SYSTEM
Table 4.1 illustrates the increasing number of putative
transmitters in the ANS besides the classic neurotransmitters
acetylcholine, noradrenaline (norepinephrine)
and adrenaline (epinephrine). These new transmitter
systems may in future lead to new therapeutic approaches
in ANS pharmacology, which is particularly interesting,
as some novel transmitter systems have a more discrete
distribution within the ANS, with the potential to
present very selective pharmacological targets with a
reduced risk of unwanted adverse effects. However, the
most detailed knowledge of the process involved in ANS
neurotransmission is available for the cholinergic (acetylcholine)
and the catecholaminergic (noradrenaline/
norepinephrine, adrenaline/epinephrine) transmitter
pathways, which will therefore be discussed in more
detail.
Neurotransmission at both cholinergic and catecholaminergic
synapses is initiated by depolarization of the
presynaptic axon terminal upon the arrival of an action
potential. This results in an influx of Ca 2+ ions, which
in turn initiates a series of protein–protein interactions
leading to the fusion of synaptic vesicles with the cell
membrane of the presynaptic axon terminal and the
release of their neurotransmitter contents into the
synaptic cleft. The transmitter then diffuses through
the synaptic space and binds to specific receptors on the
postsynaptic membrane, initiating a response in the
postsynaptic neurone. This general concept of neurotransmission
at chemical synapses, where presynaptic
neurotransmitter release causes the activation of specific
postsynaptic receptors, applies to both cholinergic and
catecholaminergic synapses. Pharmacologically important
differences do, however, exist between the mechanisms
by which the neurotransmitter is removed from
the synaptic cleft and recycled in the presynaptic terminal
in cholinergic and catecholaminergic synapses.
THE PARASYMPATHETIC NERVOUS
SYSTEM – CHOLINERGIC SYNAPSES
The general process of cholinergic neurotransmission
is the same at nicotinic and muscarinic synapses. The
activation of distinct subtypes of postsynaptic acetylcholine
receptors by the neurotransmitter actetylcholine
is responsible for the different effects on target organs.
In cholinergic nerve terminals, acetylcholine is synthesized
from choline, which is taken up into the nerve
terminal via a specific transporter, and acetyl-coenzyme-
A, a product of carbohydrate intermediate metabolism.
Transporter-mediated uptake of choline into the nerve
terminal presents the rate-limiting step of this synthetic
pathway which is catalyzed by the enzyme cholineacetyltransferase.
ACh is then pumped into secretory
vesicles via a transporter and stored until action potentials
arriving at the nerve terminal induce Ca 2+ -mediated
fusion of secretory vesicles with the presynaptic membrane
and neurotransmitter release, a process which
underlies presynaptic regulation by M 2 ACh receptors
and α 2 -adrenoceptors. ACh then diffuses across the synaptic
cleft to bind postsynaptic receptors. Ultimately,
acetylcholinesterase, a specific hydrolytic enzyme, is
responsible for the degradation of ACh in the synaptic
cleft. After ACh hydrolysis, choline is taken up into the
nerve terminal again where it is recycled.
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