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

Vascular
Injury
341
5-HT 2A
Receptor
Accelerated
Platelet
Aggregation
THROMBUS
Initial
Platelet
Aggregation
Release of 5-HT
HEMOSTASIS
VASCULAR OCCLUSION
and cerebral vasculatures. 5-HT also induces a variety of responses
by the heart that are the result of activation of multiple 5-HT receptor
subtypes, stimulation or inhibition of autonomic nerve activity, or
dominance of reflex responses to 5-HT (Kaumann and Levy, 2006).
Thus, 5-HT has positive inotropic and chronotropic actions on the
heart that may be blunted by simultaneous stimulation of afferent
nerves from baroreceptors and chemoreceptors. Activation of 5-HT 3
receptors on vagus nerve endings elicits the Bezold-Jarisch reflex,
causing extreme bradycardia and hypotension. The local response
of arterial blood vessels to 5-HT also may be inhibitory, the result of
the stimulation of endothelial NO production and prostaglandin synthesis
and blockade of norepinephrine release from sympathetic
nerves. On the other hand, 5-HT amplifies the local constrictor
actions of norepinephrine, angiotensin II, and histamine, which reinforce
the hemostatic response to 5-HT. Presumably, these constrictor
effects result, at least in part, from direct action of 5-HT on
vascular smooth muscle. In response to IV injection of 5-HT, these
disparate effects on blood pressure may be temporally distinct.
GI Tract. Enterochromaffin cells in the gastric mucosa are the site of
the synthesis and most of the storage of 5-HT in the body and are the
source of circulating 5-HT. These cells synthesize 5-HT from tryptophan,
by means of TPH1, and store 5-HT and other autacoids, such
as the vasodilator peptide substance P and other kinins. Basal release
of enteric 5-HT is augmented by mechanical stretching, such as that
caused by food, and by efferent vagal stimulation. Released 5-HT
enters the portal vein and is subsequently metabolized by MAO-A in
the liver. 5-HT that survives hepatic oxidation may be captured by
platelets or rapidly removed by the endothelium of lung capillaries
and inactivated. 5-HT released from enterochromaffin cells also acts
5-HT 1 -like
Receptor
Endothelial Release
of NO, etc.
5-HT 2A
Receptor
VASOCONSTRICTION
VASODILATION
Figure 13–4. Schematic representation of the local influences of platelet 5-HT. The release of 5-HT stored in platelets is triggered by
aggregation. The local actions of 5-HT include feedback actions on platelets (shape change and accelerated aggregation) mediated by
interaction with platelet 5-HT 2A
receptors, stimulation of NO production mediated by 5-HT 1
-like receptors on vascular endothelium,
and contraction of vascular smooth muscle mediated by 5-HT 2A
receptors. These influences act in concert with many other mediators
that are not shown to promote thrombus formation and hemostasis. See Chapter 30 for details of adhesion and aggregation of platelets
and factors contributing to thrombus formation and blood clotting.
locally to regulate GI function (Gershon and Tack, 2007). Motility
of gastric and intestinal smooth muscle may be either enhanced or
inhibited by at least six subtypes of 5-HT receptors (Table 13–3).
The stimulatory response occurs at nerve endings on longitudinal
and circular enteric muscle (5-HT 4
receptors), at postsynaptic cells
of the enteric ganglia (5-HT 3
and 5-HT 1P
receptors), and by direct
effects of 5-HT on the smooth-muscle cells (5-HT 2A
receptors in
intestine, 5-HT 2B
receptors in stomach fundus). In esophagus, 5-HT
acting at 5-HT 4
receptors causes either relaxation or contraction,
depending on the species. Abundant 5-HT 3
receptors on vagal and
other afferent neurons and on enterochromaffin cells play a pivotal
role in emesis (Chapter 46). Serotonergic nerve terminals have been
described in the myenteric plexus. Enteric 5-HT triggers peristaltic
contraction when released in response to acetylcholine, sympathetic
nerve stimulation, increases in intraluminal pressure, and lowered pH.
CNS. A multitude of brain functions are influenced by 5-HT, including
sleep, cognition, sensory perception, motor activity, temperature
regulation, nociception, mood, appetite, sexual behavior, and hormone
secretion. All of the cloned 5-HT receptors are expressed in the
brain, often in overlapping domains. Although patterns of 5-HT
receptor expression in individual neurons have not been extensively
defined, it is likely that multiple 5-HT receptor subtypes with similar
or opposing actions are expressed in individual neurons (Bonsi et
al., 2007), leading to a tremendous diversity of actions.
The principal cell bodies of 5-HT neurons are located in
raphe nuclei of the brainstem and project throughout the brain and
spinal cord (Chapter 14). In addition to being released at discrete
synapses, release of serotonin also seems to occur at sites of axonal
swelling, termed varicosities, which do not form distinct synaptic
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE