Secretory tissue—Histamine has long been recognized as a powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity, cAMP concentration, and intracellular Ca2+ concentration. Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal effects on acid output can be reduced—but not abolished—by H2-receptor antagonists. These actions are discussed in more detail in Chapter 62. Histamine also stimulates secretion in the small and large intestine. In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species.
Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations. Very high concentrations can cause catecholamine release from the adrenal medulla.
5.
Metabolic effects—Recent studies of H3-receptor knockout mice demonstrate that absence of this receptor results in increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the H3 receptor has a similar role in humans, but research is under way to determine whether H3 agonists are useful in the treatment of obesity.
6.
The “triple response”—Intradermal injection of histamine causes a characteristic red spot, edema, and flare response. The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is said to be caused by an axon reflex. A sensation of itching may accompany these effects.
Similar local effects may be produced by injecting histamine liberators (compound 48/80, morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be prevented by adequate doses of an H1-receptor-blocking agent, H2 and H3 receptors may also be involved.
7.
Other effects possibly mediated by histamine receptors— In addition to the local stimulation of peripheral pain nerve endings via H3 and H1 receptors, histamine may play a role in nociception in the central nervous system. Burimamide, an early candidate for H2-blocking action, and newer analogs with no notable effect on H1, H2, or H3 receptors, have been shown to have significant analgesic action in rodents when administered into the central nervous system. The analgesia is said to be comparable to that produced by opioids, but tolerance, respiratory depression, and constipation have not been reported.
Small substitutions on the imidazole ring of histamine significantly modify the selectivity of the compounds for the histamine receptor subtypes. Some of these are listed in Table 16–1.
In pulmonary function laboratories, histamine aerosol has rarely been used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications.
Adverse effects of histamine release, like those following administration of histamine, are dose related. Flushing, hypotension, tachycardia, headache, urticaria, bronchoconstriction, and gastrointestinal upset are noted. These effects are also observed after the ingestion of spoiled fish (scombroid fish poisoning), and histamine produced by bacterial action in the flesh of improperly stored fish is the major causative agent.
Histamine should not be given to patients with asthma (except as part of a carefully monitored test of pulmonary function) or to patients with active ulcer disease or gastrointestinal bleeding.