DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

188 in transmitter release comes from the fact that botulinum neurotoxins
and tetanus toxin, which block neurotransmitter release, proteolyze
these three proteins (Südhof, 2004).
Two pools of acetylcholine appear to exist. One pool, the
“depot” or “readily releasable” pool, consists of vesicles located near
the plasma membrane of the nerve terminals; these vesicles contain
newly synthesized transmitter. Depolarization of the terminals causes
these vesicles to release ACh rapidly or readily. The other pool, the
“reserve pool,” seems to replenish the readily releasable pool and
may be required to sustain ACh release during periods of prolonged
or intense nerve stimulation.
SECTION II
NEUROPHARMACOLOGY
Acetylcholinesterase (AChE). For ACh to serve as a
neurotransmitter in the motor system and at other
neuronal synapses, it must be removed or inactivated
within the time limits imposed by the response characteristics
of the synapse. At the neuromuscular junction,
immediate removal is required to prevent lateral diffusion
and sequential activation of adjacent receptors.
Modern biophysical methods have revealed that the
time required for hydrolysis of ACh at the neuromuscular
junction is less than a millisecond. The K m
of AChE
for ACh is ~50-100 μM. Choline has only 10 –3 to 10 –5
the potency of ACh at the neuromuscular junction.
While AChE is found in cholinergic neurons (dendrites,
perikarya, and axons), it is distributed more widely than cholinergic
synapses. It is highly concentrated at the postsynaptic end plate of
the neuromuscular junction. Butyrylcholinesterase (BuChE; also
known as pseudocholinesterase) is present in low abundance in glial
or satellite cells but is virtually absent in neuronal elements of the
central and peripheral nervous systems. BuChE is synthesized
primarily in the liver and is found in liver and plasma; its likely
physiological function is the hydrolysis of ingested esters from plant
sources. AChE and BuChE typically are distinguished by the relative
rates of ACh and butyrylcholine hydrolysis and by effects of selective
inhibitors (Chapter 10). Almost all pharmacological effects of
the anti-ChE agents are due to the inhibition of AChE, with the consequent
accumulation of endogenous ACh in the vicinity of the nerve
terminal. Distinct but single genes encode AChE and BuChE in
mammals; the diversity of molecular structure of AChE arises from
alternative mRNA processing (Taylor et al., 2000).
Numerous reports suggest that AChE plays other roles in
addition to its classical function in terminating impulse transmission
at cholinergic synapses. Non-classical functions of AChE might
include hydrolysis of ACh in a non-synaptic context, action as an
adhesion protein involved in synaptic development and maintenance,
as a bone matrix protein, involvement in neurite outgrowth, and
acceleration of the assembly of Aβ peptide into amyloid fibrils
(Silman and Sussman, 2005).
Characteristics of Cholinergic Transmission at Various
Sites. There are marked differences among various sites
of cholinergic transmission with respect to architecture
and fine structure, the distributions of AChE and receptors,
and the temporal factors involved in normal function.
In skeletal muscle, e.g., the junctional sites occupy a
small, discrete portion of the surface of the individual
fibers and are relatively isolated from those of adjacent
fibers; in the superior cervical ganglion, ~100,000 ganglion
cells are packed within a volume of a few cubic
millimeters, and both the presynaptic and postsynaptic
neuronal processes form complex networks.
Skeletal Muscle. Stimulation of a motor nerve results in the release
of ACh from perfused muscle; close intra-arterial injection of ACh
produces muscular contraction similar to that elicited by stimulation
of the motor nerve. The amount of ACh (10 –17 mol) required to elicit
an end-plate potential (EPP) following its microiontophoretic application
to the motor end plate of a rat diaphragm muscle fiber is
equivalent to that recovered from each fiber following stimulation
of the phrenic nerve.
The combination of ACh with nicotinic ACh receptors at the
external surface of the postjunctional membrane induces an immediate,
marked increase in cation permeability. On receptor activation
by ACh, its intrinsic channel opens for ~1 ms; during this interval,
~50,000 Na + ions traverse the channel. The channel-opening process
is the basis for the localized depolarizing EPP within the end plate,
which triggers the muscle AP. The latter, in turn, leads to contraction.
Following section and degeneration of the motor nerve to
skeletal muscle or of the postganglionic fibers to autonomic effectors,
there is a marked reduction in the threshold doses of the transmitters
and of certain other drugs required to elicit a response; that is,
denervation supersensitivity occurs. In skeletal muscle, this change is
accompanied by a spread of the receptor molecules from the end-plate
region to the adjacent portions of the sarcoplasmic membrane, which
eventually involves the entire muscle surface. Embryonic muscle also
exhibits this uniform sensitivity to ACh prior to innervation. Hence,
innervation represses the expression of the receptor gene by the nuclei
that lie in extrajunctional regions of the muscle fiber and directs the
subsynaptic nuclei to express the structural and functional proteins
of the synapse (Sanes and Lichtman, 1999).
Autonomic Effector Cells. Stimulation or inhibition of autonomic
effector cells occurs on activation of muscarinic acetylcholine receptors
(discussed later in the chapter). In this case, the effector is coupled
to the receptor by a G protein (Chapter 3). In contrast to skeletal
muscle and neurons, smooth muscle and the cardiac conduction system
[sinoatrial (SA) node, atrium, atrioventricular (AV) node, and
the His-Purkinje system] normally exhibit intrinsic activity, both
electrical and mechanical, that is modulated but not initiated by
nerve impulses.
In the basal condition, unitary smooth muscle exhibits waves
of depolarization and/or spikes that are propagated from cell to cell
at rates considerably slower than the AP of axons or skeletal muscle.
The spikes apparently are initiated by rhythmic fluctuations in the
membrane resting potential. Application of ACh (0.1 to 1 μM) to
isolated intestinal muscle causes a decrease in the resting potential
(i.e., the membrane potential becomes less negative) and an increase
in the frequency of spike production, accompanied by a rise in tension.
A primary action of ACh in initiating these effects through muscarinic
receptors is probably partial depolarization of the cell
membrane brought about by an increase in Na + and, in some
instances, Ca 2+ conductance. ACh also can produce contraction of