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

(“facilitated exchange diffusion”). In addition, these
amines are able to mobilize NE stored in the vesicles
by competing for the vesicular uptake process.
Reserpine, which depletes vesicular stores of NE, also
inhibits this uptake mechanism, but in contrast with
the indirect-acting sympathomimetic amines, it enters
the adrenergic nerve ending by passive diffusion
across the axonal membrane.
The actions of indirect-acting sympathomimetic amines are
subject to tachyphylaxis. For example, repeated administration of
tyramine results in rapidly decreasing effectiveness, whereas
repeated administration of NE does not reduce effectiveness and, in
fact, reverses the tachyphylaxis to tyramine. Although these phenomena
have not been explained fully, several hypotheses have been
proposed. One possible explanation is that the pool of neurotransmitter
available for displacement by these drugs is small relative to the
total amount stored in the sympathetic nerve ending. This pool is
presumed to reside in close proximity to the plasma membrane, and
the NE of such vesicles may be replaced by the less potent amine following
repeated administration of the latter substance. In any case,
neurotransmitter release by displacement is not associated with the
release of DβH and does not require extracellular Ca 2+ ; thus, it is
presumed not to involve exocytosis.
There are also three extraneuronal transporters that handle a
wide range of endogenous and exogenous substrates. The extraneuronal
amine transporter (ENT), originally named uptake-2 and
also designated OCT3, is an organic cation transporter. Relative to
NET, ENT exhibits lower affinity for catecholamines, favors epinephrine
over NE and DA, and shows a higher maximum rate of
catecholamine uptake. The ENT is not Na + - dependent and displays
a different profile of pharmacological inhibition. Other members of
this family are the organic cation transporters OCT1 and OCT2
(Chapter 5). All three can transport catecholamines in addition to a
wide variety of other organic acids, including 5-HT, histamine,
choline, spermine, guanidine, and creatinine. The characteristics and
location of the non-neuronal transporters are summarized in Table 8–5.
Release of Catecholamines. The full sequence of steps
by which the nerve impulse effects the release of NE
from sympathetic neurons is not known. In the adrenal
medulla, the triggering event is the liberation of ACh
by the preganglionic fibers and its interaction with nicotinic
receptors on chromaffin cells to produce a localized
depolarization; a subsequent step is the entrance
of Ca 2+ into these cells, which results in the extrusion
by exocytosis of the granular contents, including epinephrine,
ATP, some neuroactive peptides or their precursors,
chromogranins, and DβH. Influx of Ca 2+
likewise plays an essential role in coupling the nerve
impulse, membrane depolarization, and opening of
voltage-gated Ca 2+ channels with the release of norepinephrine
at sympathetic nerve terminals. Blockade of
N-type Ca 2+ channels leads to hypotension likely owing
to inhibition of NE release. Ca 2+ -triggered secretion
involves interaction of highly conserved molecular
scaffolding proteins leading to docking of granules at
the plasma membrane and ultimately leading to secretion
(Aunis, 1998).
Reminiscent of the release of ACh at cholinergic terminals,
various synaptic proteins, including the plasma membrane proteins
syntaxin and SNAP-25, and the vesicle membrane protein synaptobrevin
form a complex that interacts in an ATP-dependent manner
with the soluble proteins N-ethylmaleimide-sensitive fusion protein
(NSF) and soluble NSF attachment proteins (SNAPs). The ability of
synaptobrevin, syntaxin, and SNAP-25 to bind SNAPs has led to
their designation as SNAP receptors (SNAREs). It has been hypothesized
that most, if not all, intracellular fusion events are mediated
by SNARE interactions (Boehm and Kubista, 2002). As with
cholinergic neurotransmission, important evidence supporting the
involvement of SNARE proteins (e.g., SNAP-25, syntaxin, and
synaptobrevin) in transmitter release comes from the fact that botulinum
neurotoxins and tetanus toxin, which potently block neurotransmitter
release, proteolyse these proteins.
Enhanced activity of the sympathetic nervous system is
accompanied by an increased concentration of both DβH and chromogranins
in the circulation, supporting the argument that the
process of release following adrenergic nerve stimulation also
involves exocytosis.
Adrenergic fibers can sustain the output of norepinephrine
during prolonged periods of stimulation without exhausting their
reserve supply, provided that synthesis and uptake of the transmitter
are unimpaired. To meet increased needs for NE acute regulatory
mechanisms are evoked involving activation of tyrosine hydroxylase
and DβH (described earlier in the chapter).
Prejunctional Regulation of Norepinephrine Release.
The release of the three sympathetic co-transmitters can
be modulated by prejunctional autoreceptors and heteroreceptors.
Following their release from sympathetic
terminals, all three co-transmitters—NE, neuropeptide
Y (NPY), and ATP—can feed back on prejunctional
receptors to inhibit the release of each other (Westfall,
2004; Westfall et al., 2002). The most thoroughly studied
have been prejunctional α 2
adrenergic receptors.
The α 2A
and α 2C
adrenergic receptors are the principal
prejunctional receptors that inhibit sympathetic neurotransmitter
release, whereas the α 2B
adrenergic receptors
also may inhibit transmitter release at selected
sites. Antagonists of this receptor, in turn, can enhance
the electrically evoked release of sympathetic neurotransmitter.
NPY, acting on Y 2
receptors, and ATPderived
adenosine, acting on P1 receptors, also can
inhibit sympathetic neurotransmitter release. Numerous
heteroreceptors on sympathetic nerve varicosities also
inhibit the release of sympathetic neurotransmitters;
these include: M 2
and M 4
muscarinic, 5-HT, PGE 2
, histamine,
enkephalin, and DA receptors. Enhancement of
sympathetic neurotransmitter release can be produced
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS