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CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 279

Pharmacodynamics chemotactic effects on eosinophils and mast cells. In this role, they
seem to play a part in inflammation and allergy. They may also
A. Mechanism of Action modulate production of these cell types and they may mediate, in
Histamine exerts its biologic actions by combining with specific part, the previously recognized effects of histamine on cytokine
receptors located on the cell membrane. Four different histamine production.
receptors have been characterized and are designated H –H ; they
4
1
are described in Table 16–1. Unlike the other amine transmitter B. Tissue and Organ System Effects of Histamine
receptors discussed previously, no subfamilies have been found Histamine exerts powerful effects on smooth and cardiac muscle,
within these major types, although different splice variants of on certain endothelial and nerve cells, on the secretory cells of
several receptor types have been described. the stomach, and on inflammatory cells. However, sensitivity to
All four receptor types have been cloned and belong to the histamine varies greatly among species. Guinea pigs are exquisitely
large superfamily of G protein-coupled receptors (GPCR). The sensitive; humans, dogs, and cats somewhat less so; and mice and
structures of the H and H receptors differ significantly and rats very much less so.
1
2
appear to be more closely related to muscarinic and 5-HT
1
receptors, respectively, than to each other. The H receptor has 1. Nervous system—Histamine is a powerful stimulant of
4
about 40% homology with the H receptor but does not seem sensory nerve endings, especially those mediating pain and
3
to be closely related to any other histamine receptor. All four itching. This H -mediated effect is an important component of
1
histamine receptors have been shown to have constitutive activity the urticarial response and reactions to insect and nettle stings.
in some systems; thus, some antihistamines previously considered to Some evidence suggests that local high concentrations can also
be traditional pharmacologic antagonists must now be considered depolarize efferent (axonal) nerve endings (see Triple Response,
to be inverse agonists (see Chapters 1 and 2). Indeed, many first- item 8 in this list). In the mouse, and probably in humans, respi-
and second-generation H blockers function as inverse agonists. ratory neurons signaling inspiration and expiration are modulated
1
Furthermore, a single molecule may be an agonist at one hista- by H receptors. H and H receptors play important roles in
3
1
1
mine receptor and an antagonist or inverse agonist at another. For appetite and satiety; antipsychotic drugs that block these receptors
example, clobenpropit, an agonist at H receptors, is an antagonist cause significant weight gain (see Chapter 29). These receptors
4
or inverse agonist at H receptors (Table 16–1). may also participate in nociception. Presynaptic H receptors play
3
3
In the brain, H and H receptors are located on postsynaptic important roles in modulating release of several transmitters in
1
2
membranes, whereas H receptors are predominantly presynaptic. the nervous system. H agonists reduce the release of acetylcho-
3
3
Activation of H receptors, which are present in endothelium, line, amine, and peptide transmitters in various areas of the brain
1
smooth muscle cells, and nerve endings, usually elicits an increase and in peripheral nerves. An investigational inverse H agonist,
3
in phosphoinositol hydrolysis and an increase in inositol trispho- pitolisant (BF2649), appears to reduce drowsiness in patients
sphate (IP ) and intracellular calcium. Activation of H receptors, with narcolepsy.
2
3
present in gastric mucosa, cardiac muscle cells, and some immune
cells, increases intracellular cyclic adenosine monophosphate 2. Cardiovascular system—In humans, injection or infusion
(cAMP) via G . Like the β adrenoceptor, under certain circum- of histamine causes a decrease in systolic and diastolic blood pres-
2
s
stances the H receptor may couple to G , activating the IP -DAG sure and an increase in heart rate. The blood pressure changes are
q
3
2
(inositol 1,4,5-trisphosphate-diacylglycerol) cascade. Activation caused by the vasodilator action of histamine on arterioles and
of H receptors decreases transmitter release from histaminergic precapillary sphincters; the increase in heart rate involves both
3
and other neurons, probably mediated by a decrease in calcium stimulatory actions of histamine on the heart and a reflex tachy-
influx through N-type calcium channels in nerve endings. H cardia. Flushing, a sense of warmth, and headache may also occur
4
receptors are found mainly on leukocytes in the bone marrow during histamine administration, consistent with the vasodila-
and circulating blood. H receptors appear to have very important tion. Vasodilation elicited by small doses of histamine is caused
4
TABLE 16–1 Histamine receptor subtypes.
Receptor Postreceptor Partially Selective Partially Selective Antagonists or
Subtype Distribution Mechanism Agonists Inverse Agonists
1
Smooth muscle, endothelium, brain G q, ↑ IP 3, DAG Histaprodifen Mepyramine, triprolidine, cetirizine
H 1
1
1
Gastric mucosa, cardiac muscle, mast cells, brain G s, ↑ cAMP Amthamine Cimetidine, ranitidine, tiotidine
H 2
1
H 3 Presynaptic autoreceptors and heteroreceptors: G i, ↓ cAMP R-α-Methylhistamine, Thioperamide, iodophenpropit,
1
1
brain, myenteric plexus, other neurons imetit, immepip clobenpropit, tiprolisant, proxyfan
Eosinophils, neutrophils, CD4 T cells G i, ↓ cAMP Clobenpropit, imetit, Thioperamide 1
H 4
clozapine
1
Inverse agonist.
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP 3 , inositol trisphosphate.