Page 294 - Basic _ Clinical Pharmacology ( PDFDrive )

280 SECTION IV Drugs with Important Actions on Smooth Muscle

by H -receptor activation and is mediated mainly by release of genitourinary tract. However, pregnant women suffering
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nitric oxide from the endothelium (see Chapter 19). The decrease anaphylactic reactions may abort as a result of histamine-
in blood pressure is usually accompanied by a reflex tachycardia. induced contractions, and in some species the sensitivity of the
Higher doses of histamine activate the H -mediated cAMP process uterus is sufficient to form the basis for a bioassay.
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of vasodilation and direct cardiac stimulation. In humans, the 4. Secretory tissue—Histamine has long been recognized as a
cardiovascular effects of small doses of histamine can usually be powerful stimulant of gastric acid secretion and, to a lesser
antagonized by H -receptor antagonists alone. extent, of gastric pepsin and intrinsic factor production. The
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Histamine-induced edema results from the action of the effect is caused by activation of H receptors on gastric parietal
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amine on H receptors in the vessels of the microcirculation, cells and is associated with increased adenylyl cyclase activity,
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2+
especially the postcapillary vessels. The effect is associated cAMP concentration, and intracellular Ca concentration.
with the separation of the endothelial cells, which permits Other stimulants of gastric acid secretion such as acetylcholine
the transudation of fluid and molecules as large as small and gastrin do not increase cAMP even though their maximal
proteins into the perivascular tissue. This effect is responsible effects on acid output can be reduced—but not abolished—by
for urticaria (hives), which signals the release of histamine in H -receptor antagonists. These actions are discussed in more
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the skin. Studies of endothelial cells suggest that actin and detail in Chapter 62. Histamine also stimulates secretion in the
myosin within these cells cause contraction, resulting in separa- small and large intestine. In contrast, H -selective histamine
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tion of the endothelial cells and increased permeability. agonists inhibit acid secretion stimulated by food or pentagas-
Direct cardiac effects of histamine include both increased trin in several species.
contractility and increased pacemaker rate. These effects are Histamine has much smaller effects on the activity of
mediated chiefly by H receptors. In human atrial muscle, other glandular tissue at ordinary concentrations. Very high
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histamine can also decrease contractility; this effect is medi- concentrations can cause catecholamine release from the
ated by H receptors. The physiologic significance of these adrenal medulla.
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cardiac actions is not clear. Some of the cardiovascular signs 5. Metabolic effects—Recent studies of H -receptor knockout
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and symptoms of anaphylaxis are due to released histamine, mice demonstrate that absence of this receptor results in
although several other mediators are involved and are much increased food intake, decreased energy expenditure, and
more important than histamine in humans. obesity. They also show insulin resistance and increased blood
1. Bronchiolar smooth muscle—In both humans and guinea levels of leptin and insulin. It is not yet known whether the
pigs, histamine causes bronchoconstriction mediated by H receptor has a similar role in humans, but research is under
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H receptors. In the guinea pig, this effect is the cause of death way to determine whether H agonists are useful in the
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from histamine toxicity, but in humans with normal airways, treatment of obesity.
bronchoconstriction following small doses of histamine is not 6. The “triple response”—Intradermal injection of histamine
marked. However, patients with asthma are very sensitive to causes a characteristic red spot, edema, and flare response. The
histamine. The bronchoconstriction induced in these patients effect involves three separate cell types: smooth muscle in the
probably represents a hyperactive neural response, since such microcirculation, capillary or venular endothelium, and
patients also respond excessively to many other stimuli, and the sensory nerve endings. At the site of injection, a reddening
response to histamine can be blocked by autonomic block- appears owing to dilation of small vessels, followed soon by an
ing drugs such as ganglion blocking agents as well as by edematous wheal at the injection site and a red irregular flare
H -receptor antagonists (see Chapter 20). Although methacho- surrounding the wheal. The flare is said to be caused by an axon
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line provocation is more commonly used, tests using small reflex. A sensation of itching may accompany these effects.
doses of inhaled histamine have been used in the diagnosis of Similar local effects may be produced by injecting histamine
bronchial hyperreactivity in patients with suspected asthma or liberators (compound 48/80, morphine, etc) intradermally or
cystic fibrosis. Such individuals may be 100 to 1000 times by applying the appropriate antigens to the skin of a sensitized
more sensitive to histamine (and methacholine) than are person. Although most of these local effects can be prevented
normal subjects. Curiously, a few species (eg, rabbit) respond -receptor-blocking agent, H and
to histamine with bronchodilation, reflecting the dominance of by adequate doses of an H 1 2
H receptors may also be involved.
receptor in their airways. 3
the H 2
7. Other effects possibly mediated by histamine receptors—
2. Gastrointestinal tract smooth muscle—Histamine causes In addition to the local stimulation of peripheral pain nerve
contraction of intestinal smooth muscle, and histamine- endings via H and H receptors, histamine may play a role
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induced contraction of guinea pig ileum is a standard bioassay in nociception in the central nervous system. Burimamide, an
for this amine. The human gut is not as sensitive as that of the early candidate for H -blocking action, and newer analogs with
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guinea pig, but large doses of histamine may cause diarrhea, no notable effect on H , H , or H receptors, have been shown
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partly as a result of this effect. This action of histamine is to have significant analgesic action in rodents when adminis-
mediated by H receptors. tered into the central nervous system. The analgesia is said to be
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3. Other smooth muscle organs—In humans, histamine generally comparable to that produced by opioids, but tolerance, respira-
has insignificant effects on the smooth muscle of the eye and tory depression, and constipation have not been reported.