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

916 of H receptor subtypes on neighboring cells and the
unequal sensitivities of H receptor–effector response pathways
can cause parallel and opposing cellular responses
to occur together, complicating interpretation of the overall
response of a tissue. For example, activation of H 1
receptors on vascular endothelium stimulates the Ca 2+ -
mobilizing pathway (G q
–PLC–IP 3
) and activates eNOS
to produce nitric oxide (NO), which diffuses to nearby
smooth muscle cells to increase cyclic GMP and cause
relaxation. Stimulation of H 1
receptors on smooth muscle
also will mobilize Ca 2+ but cause contraction, whereas
activation of H 2
receptors on the same smooth muscle cell
will link via G s
to enhanced cyclic AMP accumulation,
activation of PKA, and thence to relaxation.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
The existence of multiple histamine receptors was predicted
by the studies of Ash and Schild (1966) and Black and colleagues
(1972) a generation before the cloning of histamine receptors.
Similarly, heterogeneity of H 3
receptors, predicted by kinetic and
radioligand-binding studies, has been confirmed by cloning, which
revealed H 3
isoforms differing in the third intracellular loop, transmembrane
helices 6 and 7, and C-terminal tail, and in their capacity
to couple G i
, inhibit adenylyl cyclase, and activate MAP kinase.
Molecular cloning studies also identified the H 4
receptor.
As Figure 32–1 and Table 32–1 indicate, the pharmacological
definition of H 1
, H 2
, and H 3
receptors is clear because relatively
specific agonists and antagonists are available. However, the H 4
receptor exhibits 35-40% homology to isoforms of the H 3
receptor,
and the two were harder to distinguish pharmacologically because
many high-affinity H 3
ligands also interact with H 4
receptors. Several
non-imidazole compounds that are more selective H 3
antagonists
have been developed (Sander et al., 2008), and there are now several
selective H 4
antagonists (Leurs et al., 2009; Venable and Thurmond,
2006). 4-Methylhistamine and dimaprit, previously identified as specific
H 2
agonists (Black et al., 1972), are actually more potent H 4
agonists (Venable and Thurmond, 2006).
H 1
and H 2
Receptors. H 1
and H 2
receptors are distributed
widely in the periphery and in the CNS.
Histamine can exert local or widespread effects on
smooth muscles and glands. It causes itching and stimulates
secretion from nasal mucosa. It contracts many
smooth muscles, such as those of the bronchi and gut,
but markedly relaxes others, including those in small
blood vessels. Histamine also is a potent stimulus of
gastric acid secretion (see “Gastric Acid Secretion”).
Other, less prominent effects include formation of
edema and stimulation of sensory nerve endings.
Bronchoconstriction and contraction of the gut are
mediated by H 1
receptors. Gastric secretion results
from the activation of H 2
receptors and, accordingly,
can be inhibited by H 2
receptor antagonists. Some
responses, such as vascular dilation, are mediated by
both H 1
and H 2
receptor stimulation.
H 3
and H 4
Receptors. H 3
receptors are expressed mainly
in the CNS (Arrang et al., 1987), especially in the basal
ganglia, hippocampus, and cortex. H 3
receptors function
as autoreceptors on histaminergic neurons, much
like presynaptic α 2
receptors, inhibiting histamine release
and modulating the release of other neurotransmitters.
Because H 3
receptors have high constitutive activity,
histamine release is tonically inhibited, and inverse agonists
will thus reduce receptor activation and increase
histamine release from histaminergic neurons. H 3
agonists
promote sleep; thus, H 3
antagonists promote
wakefulness. H 4
receptors primarily are found in cells
of hematopoietic origin such as eosinophils, dendritic
cells, mast cells, monocytes, basophils, and T cells but
has also been detected in the GI tract, dermal fibroblasts,
CNS, and primary sensory afferent neurons
(Leurs et al., 2009). Activation of H 4
receptors in some
of these cell types has been associated with induction of
cellular shape change, chemotaxis, secretion of
cytokines and upregulation of adhesion molecules, suggesting
that H 4
antagonists may be useful inhibitors of
allergic and inflammatory responses (Thurmond et al.,
2008.
Effects on Histamine Release. H 2
receptor stimulation
increases cyclic AMP and leads to feedback inhibition
of histamine release from mast cells and basophils,
whereas activation of H 3
and H 4
receptors has the opposite
effect by decreasing cellular cyclic AMP (Oda et al.,
2000). Activation of presynaptic H 3
receptors also
inhibits histamine release from histaminergic neurons.
Histamine Toxicity from Ingestion. Histamine is the toxin in food poisoning
from spoiled scombroid fish such as tuna (Morrow et al.,
1991). The high histidine content combines with a large bacterial
capacity to decarboxylate histidine, generating a lot of histamine.
Ingestion of the fish causes severe nausea, vomiting, headache, flushing,
and sweating. Histamine toxicity, manifested by headache and
other symptoms, also can follow red wine consumption in persons
with a diminished ability to degrade histamine. The symptoms of histamine
poisoning can be suppressed by H 1
antagonists.
Cardiovascular System. Histamine characteristically
dilates resistance vessels, increases capillary permeability,
and lowers systemic blood pressure. In some vascular
beds, histamine constricts veins, contributing to the
extravasation of fluid and edema formation upstream
in capillaries and postcapillary venules.
Vasodilation. This is the most important vascular effect
of histamine in humans. Vasodilation involves both H 1
and H 2
receptors distributed throughout the resistance
vessels in most vascular beds; however, quantitative differences
are apparent in the degree of dilation that
occurs in various beds. Activation of either the H 1
or H 2