Page 292 - Basic _ Clinical Pharmacology ( PDFDrive )

278 SECTION IV Drugs with Important Actions on Smooth Muscle

■ HISTAMINE of the stomach. ECL cells release histamine, one of the primary
gastric acid secretagogues, to activate the acid-producing parietal
Histamine was synthesized in 1907 and later isolated from cells of the mucosa (see Chapter 62).
mammalian tissues. Early hypotheses concerning the possible
physiologic roles of tissue histamine were based on similarities Storage & Release of Histamine
between the effects of intravenously administered histamine and The stores of histamine in mast cells can be released through
the symptoms of anaphylactic shock and tissue injury. Marked several mechanisms.
species variation is observed, but in humans histamine is an
important mediator of immediate allergic (such as urticaria) and A. Immunologic Release
inflammatory reactions, although it plays only a modest role in
anaphylaxis. Histamine plays an important role in gastric acid Immunologic processes account for the most important patho-
secretion (see Chapter 62) and functions as a neurotransmitter physiologic mechanism of mast cell and basophil histamine
and neuromodulator (see Chapters 6 and 21). Newer evidence release. These cells, if sensitized by IgE antibodies attached
indicates that histamine also plays a role in immune functions and to their surface membranes, degranulate explosively when
chemotaxis of white blood cells. exposed to the appropriate antigen (see Figure 55–5, effector
phase). This type of release also requires energy and calcium.
Degranulation leads to the simultaneous release of histamine,
BASIC PHARMACOLOGY OF HISTAMINE adenosine triphosphate (ATP), and other mediators that are
stored together in the granules. Histamine released by this
Chemistry & Pharmacokinetics mechanism is a mediator in immediate (type I) allergic reac-
tions, such as hay fever and acute urticaria. Substances released
Histamine occurs in plants as well as in animal tissues and is a during IgG- or IgM-mediated immune reactions that activate
component of some venoms and stinging secretions. the complement cascade also release histamine from mast cells
Histamine is formed by decarboxylation of the amino acid and basophils.
l-histidine, a reaction catalyzed in mammalian tissues by the By a negative feedback control mechanism mediated by H
2
enzyme histidine decarboxylase. Once formed, histamine is either receptors, histamine appears to modulate its own release and that
stored or rapidly inactivated. Very little histamine is excreted of other mediators from sensitized mast cells in some tissues.
unchanged. The major metabolic pathways involve conversion to In humans, mast cells in skin and basophils show this negative
N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic feedback mechanism; lung mast cells do not. Thus, histamine
acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pig- may act to limit the intensity of the allergic reaction in the skin
mentosa, gastric carcinoid, and occasionally myelogenous leukemia) and blood.
are associated with increased numbers of mast cells or basophils and Endogenous histamine has a modulating role in a variety of
with increased excretion of histamine and its metabolites.
inflammatory and immune responses. Upon injury to a tissue,
released histamine causes local vasodilation and leakage of
CH 2 CH 2 NH 2 plasma-containing mediators of acute inflammation (comple-
HN N ment, C-reactive protein) and antibodies. Histamine has an
active chemotactic attraction for inflammatory cells (neutrophils,
Histamine eosinophils, basophils, monocytes, and lymphocytes). Histamine
inhibits the release of lysosome contents and several T- and
Most tissue histamine is sequestered and bound in granules B-lymphocyte functions. Most of these actions are mediated by
(vesicles) in mast cells or basophils; the histamine content of H or H receptors. Release of peptides from nerves in response to
2
4
many tissues is directly related to their mast cell content. The inflammation is also probably modulated by histamine acting on
bound form of histamine is biologically inactive, but as noted presynaptic H 3 receptors.
below, many stimuli can trigger the release of mast cell histamine,
allowing the free amine to exert its actions on surrounding tissues. B. Chemical and Mechanical Release
Mast cells are especially rich at sites of potential tissue injury— Certain amines, including drugs such as morphine and tubocu-
nose, mouth, and feet; internal body surfaces; and blood vessels, rarine, can displace histamine from its bound form within cells.
particularly at pressure points and bifurcations. This type of release does not require energy and is not associ-
Non-mast cell histamine is found in several tissues, includ- ated with mast cell injury or explosive degranulation. Loss of
ing the brain, where it functions as a neurotransmitter. Strong granules from the mast cell also releases histamine, because
evidence implicates endogenous neurotransmitter histamine in sodium ions in the extracellular fluid rapidly displace the
many brain functions such as neuroendocrine control, cardio- amine from the complex. Chemical and mechanical mast cell
vascular regulation, thermal and body weight regulation, and sleep injury causes degranulation and histamine release. Compound
and arousal (see Chapter 21). 48/80, an experimental drug, selectively releases histamine
A second important nonneuronal site of histamine storage from tissue mast cells by an exocytotic degranulation process
and release is the enterochromaffin-like (ECL) cells of the fundus requiring energy and calcium.