Receptor
Subtype
|
Localization
|
Receptor
coupling
|
Antagonists
(partially selective)
|
H1
|
endothelium,
brain, smooth muscle
|
 IP3,
DAG
|
N/A
|
H2
|
mast
cells, gastric mucosa, cardiac muscle, brain
|
cAMP
|
ranitidine
(Zantac), tiotidine
|
H3
|
presynaptic:
brain, mesenteric plexus (other neurons)
|
G
protein coupled
|
N/A
|
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- Receptor subtypes --
- intracellular G protein
interactions
- H1:
--endothelial and smooth muscle cell localization
- activation causes
- phosphoinositol
hydrolysis
- increase
intracellular calcium
- H2 -- gastric
mucosa, cardiac muscle cells, immune cell
localization:
- activation causes
- cAMP
- H3: primarily
presynaptic
- activation causes
 transmitter release
{transmitters: histamine,acetylcholine, norepinephrine,
serotonin)
- decrease may be due to
reduced calcium influx (N-type
calcium channel)
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Organ System Effects
- Cardiovascular:
- systolic
and diastolic blood pressure
- histamine
vasodilates acting: on arterioles
and precapillary sphincters
- vasodilation
due in part to nitric oxide
(endothelium-derived relaxing
factor, EDRF)
- heart
rate
- reflex
tachycardia
- direct
action
- Both H1
and H2
receptors involved in cardiovascular
responses.
- Histamine-associated
edema:H1
receptor effects (postcapillary vessels)
- increase
in vessel permeability due to
separation of endothelial cells,
allowing transudation of fluid
and molecules as large as small
proteins.
- responsible
for urticaria (hives)
- endothelial
cell separation:
secondary to
histamine-induced calcium
influx causing
intracellular actin/myosin-mediated
contraction
- Direct cardiac
effects:
- increased
contractility (positive inotropism)
- increased
pacemaker rate (positive chronotropism)
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- Bronchiolar smooth muscle
- H1 receptor mediated
bronchoconstriction
- inhaled histamine:diagnostic, provocative test
for bronchial hyperreactivity (asthma or
cystic fibrosis)
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- Nerve
Endings:
- sensory nerve ending stimulant
(particularly endings mediating pain and
itching)
- H1 receptor
mediated effect: part of local reaction
to insect stings; urticarial responses
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- Secretory
tissue:
- Stimulant:
- gastric acid
secretion (significant stimulant)
- gastric pepsin
- intrinsic factor
production
- Mechanism of Action:
- H2
receptor mediated effects on gastric
parietal cells
- adenylyl cyclase
activity,cAMP, intracellular calcium
- (acetylcholine
and gastrin stimulate gastric
acid released but do not increase
cyclic AMP)
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- Triple
Response:
- intradermal histamine
injection: wheal-and-flare-- three cell
types
- smooth muscle in the
microcirculation
- endothelium: capillary or
venular
- sensory nerve endings
- Sequence following
histamine injection
- reddening (small
vessel dilatation)
- edematous wheal
(injection site)
- flare (irregular,
surrounding wheal) -- caused by
axon reflex
- Wheal-and-flare effects
can be induced by histamine releasing
agents (agents 48/80, morphine, etc.) --
mainly an H1 receptor-mediated
effect
Some Histamine H2
Receptor Agonists
Betazole
|
Impromidine
|
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- Histamine:Clinical Pharmacology-- uses
historical: test for gastric
acid secreting capability (pentagastrin, currently used)-
historical: diagnosis
of pheochromocytoma (histamine
promotes substantial catecholamine
release) -- direct measurement of
catecholamine and catecholamine
metabolite concentration is now
performed:
-
Pulmonary Function:
histamine aerosol may be used to test for
bronchial hyperreactivity.
- Toxicity:
-
Flushing, hypotension, tachycardia, headache,
bronchoconstriction, gastrointestinal
disturbances
- should not be given to
asthmatics (except with extreme caution
in pulmonary function testing)
- should not be given to
patients with active ulcer disease or
gastrointestinal hemorrhage.
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