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

of acid, and moderate bronchospasm also frequently occur. The
effect becomes less intense with successive injections as the mast
cell stores of histamine are depleted. Histamine liberators do not
deplete tissues of non–mast cell histamine.
Mechanism of Histamine-Releasing Agents. Histaminereleasing
substances activate the secretory responses of
mast cells and basophils by causing a rise in intracellular
Ca 2+ . Some are ionophores and directly facilitate the entry
of Ca 2+ into the cell; others, such as neurotensin, act on
specific G protein–coupled receptors (GPCRs). In contrast,
the precise mechanism by which basic secretagogues
(e.g., substance P, mastoparan, kallidin,
compound 48/80, and polymyxin B) release histamine
still is unclear. These agents can directly activate G i
proteins
after being taken up by the cell (Ferry et al., 2002),
but more recent evidence indicates the involvement of a
cell-surface GPCR in the Mas-related gene family or integrin-associated
protein CD47 coupled to G i
(Sick et al.,
2009). The downstream effectors appear to be βγ subunits
released from Gα i
, which activate the PLCβ–IP 3
–Ca 2+
pathway. Antigen–IgE complexes lead to mobilization of
stored Ca 2+ and activation of isoforms of PLCγ, as
described in “Role in Allergic Responses.”
Histamine Release by Other Means. Clinical conditions related to
histamine release include cold, cholinergic, and solar urticaria. Some
of these involve specific secretory responses of the mast cells and
cell-fixed IgE. However, nonspecific cellular damage from any cause
can release histamine. The redness and urticaria that follow scratching
of the skin is a familiar example.
Increased Proliferation of Mast Cells and Basophils and Gastric
Carcinoid Tumors. In urticaria pigmentosa (cutaneous mastocytosis),
mast cells aggregate in the upper corium and give rise to pigmented
cutaneous lesions that sting when stroked. In systemic
mastocytosis, overproliferation of mast cells also is found in other
organs. Patients with these syndromes suffer a constellation of signs
and symptoms attributable to excessive histamine release, including
urticaria, dermographism, pruritus, headache, weakness, hypotension,
flushing of the face, and a variety of GI effects, such as diarrhea
or peptic ulceration. Episodes of mast cell activation with
attendant systemic histamine release are precipitated by a variety of
stimuli, including exertion, insect stings, exposure to heat, and exposure
to drugs that release histamine directly or to which patients are
allergic. In myelogenous leukemia, excessive numbers of basophils
are present in the blood, raising its histamine content to high levels
that may contribute to chronic pruritus. Gastric carcinoid tumors
secrete histamine, which is responsible for episodes of vasodilation
as part of the patchy “geographical” flush.
Gastric Acid Secretion. Histamine acting at H 2
receptors is a powerful
gastric secretagogue, evoking a copious secretion of acid from
parietal cells (see Figure 45–1); it also increases the output of pepsin
and intrinsic factor. The secretion of gastric acid from parietal cells
also is caused by stimulation of the vagus nerve and by the enteric
hormone gastrin. However, histamine undoubtedly is the dominant
physiological mediator of acid secretion; blockade of H 2
receptors
not only antagonizes acid secretion in response to histamine but also
inhibits responses to gastrin and vagal stimulation. (For regulation of
gastric acid secretion and the clinical utility of H 2
antagonists, see
Chapter 45.)
Central Nervous System. There is substantial evidence that histamine
functions as a neurotransmitter in the CNS. Histamine-containing
neurons control both homeostatic and higher brain functions, including
regulation of the sleep-wake cycle, circadian and feeding
rhythms, immunity, learning, memory, drinking, and body temperature
(see Haas et al., 2008). However, knockout animals lacking histamine
or its receptors exhibit only subtle defects unless challenged,
and no human disease has yet been directly linked to dysfunction of
the brain histamine system. Histamine, histidine decarboxylase,
enzymes that metabolize histamine, and H 1
, H 2
, and H 3
receptors are
distributed widely but non-uniformly in the CNS (see Haas et al.,
2008). H 1
receptors are associated with both neuronal and nonneuronal
elements (e.g., glia, blood cells, vessels) and are concentrated
in regions that control neuroendocrine function, behavior, and
nutritional state. Distribution of H 2
receptors is more consistent with
histaminergic projections than H 1
receptors, suggesting that they
mediate many of the postsynaptic actions of histamine. H 3
receptors
also are heterogeneously concentrated in areas known to receive histaminergic
projections, consistent with their function as presynaptic
autoreceptors. Histamine inhibits appetite and increases wakefulness
via H 1
receptors, explaining sedation by classical antihistamines
(Haas et al., 2008).
Pharmacological Effects
Receptor–Effector Coupling and Mechanisms of Action.
Histamine receptors are GPCRs (Leurs et al., 2009; Haas
et al., 2008; Thurmond et al., 2008) (Table 32–1). H 1
receptors couple to G q/11
and activate the PLC–IP 3
–Ca 2+
pathway and its many possible sequelae, including
activation of PKC, Ca 2+ – calmodulin– dependent enzymes
(eNOS and various protein kinases), and PLA 2
. H 2
receptors
link to G s
to activate the adenylyl cyclase–cyclic
AMP–PKA pathway, whereas H 3
and H 4
receptors couple
to G i/o
to inhibit adenylyl cyclase and decrease cellular
cyclic AMP. Activation of H 3
receptors also can
activate MAP kinase and inhibit the Na + /H + exchanger,
and activation of H 4
receptors mobilizes stored Ca 2+ in
some cells (Leurs et al., 2009; Haas et al., 2008;
Thurmond et al., 2008; Esbenshade et al., 2008). Armed
with this information, knowledge of the cellular expression
of H receptor subtypes, and an understanding of the
differentiated functions of a particular cell type, one can
predict a cell’s response to histamine. Of course, in a
physiological setting, a cell is exposed to a myriad of hormones
simultaneously, and significant interactions may
occur between signaling pathways, such as the G q
→ G s
cross-talk described in a number of systems (Meszaros
et al., 2000). Furthermore, the differential expression
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CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS