Page 107 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 6 Introduction to Autonomic Pharmacology 93

Sympathetic Sacral Outflow

As noted in the previous editions of this book and other stan- not. Sacral preganglionic neurons do express transcription fac-
dard texts, it has long been believed that, like the cranial nerve tor Foxp1, which is not expressed by cranial neurons. (2) Cranial
cholinergic system described earlier, the cholinergic nerves that parasympathetic preganglionic fibers exit the CNS via dorsolat-
innervate the pelvic organs (rectum, bladder, and reproduc- eral exit points; the sympathetic and sacral preganglionic nerves
tive organs) are part of the parasympathetic nervous system. exit the spinal cord via ventral root exits. (3) At an early stage of
However, a recent study (see Espinoza-Medina reference at development, cranial preganglionic neurons express the vesicu-
the end of this chapter) suggests that the preganglionic sacral lar acetylcholine transporter (VAChT; VAT in Figure 6–3) but not
fibers are actually derived from embryonic sympathetic precur- nitric oxide synthase (NOS); sympathetic and sacral nerves at
sor cells and that the postganglionic fibers innervated by them the same stage express NOS but not VAChT (even though they
are therefore members of the sympathetic cholinergic class. This do express VAChT later in their development). These observa-
claim is based on several lines of evidence, as follows: (1) Cranial tions require independent confirmation but constitute strong
parasympathetic preganglionic neurons express the homeo- evidence in favor of changing the traditional “craniosacral”
gene Phox2b and the transcription factors Tbx20, Tbx2, and synonym for the parasympathetic nervous system to “cranial
Tbx3; thoracic sympathetic and sacral preganglionic neurons do autonomic” nervous system.

Effects are thus slower in onset, and discharge of a single motor Cholinergic Transmission
fiber often activates or inhibits many effector cells.
The terminals and varicosities of cholinergic neurons contain
large numbers of small membrane-bound vesicles concentrated
NEUROTRANSMITTER CHEMISTRY OF near the portion of the cell membrane facing the synapse
THE AUTONOMIC NERVOUS SYSTEM (Figure 6–3) as well as a smaller number of large dense-cored
vesicles located farther from the synaptic membrane. The large
An important traditional classification of autonomic nerves is vesicles contain a high concentration of peptide cotransmitters
based on the primary transmitter molecules—acetylcholine or (Table 6–1), whereas the smaller clear vesicles contain most of
norepinephrine—released from their terminals and varicosities. the acetylcholine. Vesicles may be synthesized in the neuron cell
A large number of peripheral ANS fibers synthesize and release body and carried to the terminal by axonal transport. They may
acetylcholine; they are cholinergic fibers; that is, they work by also be recycled several times within the terminal after each exo-
releasing acetylcholine. As shown in Figure 6–1, these include all cytotic release of transmitter. Ultra-fast neuronal firing appears
preganglionic efferent autonomic fibers and the somatic (nonau- to be supported by rapid recycling of clathrin-coated vesicles
tonomic) motor fibers to skeletal muscle as well. Thus, almost all from endosomes in the nerve terminal. Vesicles are provided
efferent fibers leaving the CNS are cholinergic. In addition, most with vesicle-associated membrane proteins (VAMPs), which
parasympathetic postganglionic and some sympathetic postgan- serve to align them with release sites on the inner neuronal cell
glionic fibers are cholinergic. A significant number of parasympa- membrane and participate in triggering the release of transmit-
thetic postganglionic neurons use nitric oxide or peptides as the ter. The release site on the inner surface of the nerve terminal
primary transmitter or as cotransmitters. membrane contains synaptosomal nerve-associated proteins
Most postganglionic sympathetic fibers (Figure 6–1) release (SNAPs), which interact with VAMPs. VAMPs and SNAPs are
norepinephrine (also known as noradrenaline); they are norad- collectively called fusion proteins.
renergic (often called simply “adrenergic”) fibers; that is, they Acetylcholine (ACh) is synthesized in the cytoplasm from
work by releasing norepinephrine (noradrenaline). As noted, acetyl-CoA and choline through the catalytic action of the enzyme
some sympathetic fibers release acetylcholine. Dopamine is a very choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in
important transmitter in the CNS, and it may be released by some mitochondria, which are present in large numbers in the nerve
peripheral sympathetic fibers under certain circumstances. Adre- ending. Choline is transported from the extracellular fluid into
nal medullary cells, which are embryologically analogous to post- the neuron terminal by a sodium-dependent membrane choline
ganglionic sympathetic neurons, release a mixture of epinephrine transporter (CHT; Figure 6–3). This symporter can be blocked
and norepinephrine. Finally, most autonomic nerves also release by a group of research drugs called hemicholiniums. Once syn-
several cotransmitter substances (described in the following text), thesized, acetylcholine is transported from the cytoplasm into the
in addition to the primary transmitters just described. vesicles by a vesicle-associated transporter (VAT) that is driven
Five key features of neurotransmitter function provide poten- by proton efflux (Figure 6–3). This antiporter can be blocked by
tial targets for pharmacologic therapy: synthesis, storage, release, the research drug vesamicol. Acetylcholine synthesis is a rapid
termination of action of the transmitter, and receptor effects. process capable of supporting a very high rate of transmitter
These processes are discussed next. release. Storage of acetylcholine is accomplished by the packaging