Pharmacologic effects

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Localized allergic reactions to food or aeroallergens are generally confined to particular target organs, such as the airways, eye, gut and skin. However, more generalized, systemic responses may occur, typically in anaphylactic or anaphylactoid reactions to various drugs, agents used in surgical or preoper-




L-Histidine decarboxylase



W-Methyl transferase

Diamine oxidase

/CH2CH2NH2 CHa-N^N N T-Methylhistamine

Monoamine oxidase




Imidazole acetic acid

CHa-N^N N T -Methylimidazole acetic acid

Figure 1 Synthesis and catabolism of histamine.

ative procedures such as anesthetics and their vehicles, plasma substitutes and radiographic contrast media, and to certain insect stings, particularly those of the bee.

Anaphylactic reactions in humans are accompanied by a sharp rise in the plasma concentration of histamine and the classical signs of intoxication by the amine. The clinical manifestations may vary considerably in severity. Mild cutaneous reactions involving erythema, urticaria and pruritus, often accompanied by metallic taste, headache and nasal congestion, are associated with plasma histamine levels below 1 ng ml-1. Systemic responses with generalized skin reactions, discomfort, gastrointestinal disturbance, tachycardia, cardiac arrhythmias and medium hypotension involve elevations in plasma histamine above this basal level. Life-threat-ening responses comprising severe hypotension, ventricular fibrillation, bronchospasm and cardiac and respiratory arrest are typically associated with plasma histamine levels in excess of 12 ng ml 1 (Table 1). These responses may be most conveniently discussed in terms of the various systems involved.

Cardiovascular system

The hemodynamic response to histamine involves an effect of the amine on the blood vessels and a direct action on the heart. In humans, and most but not all other animals, histamine has a predominantly dilator effect on the peripheral blood vessels. This dilatation results in a characteristic flushing, a decrease in total peripheral vascular resistance and a fall in blood pressure. Both H, and H, receptors appear to be involved in these responses, with H, receptors largely mediating the initial vasodilator cffect and H, receptors becoming progressively involved during sustained exposure to the amine.

The above, and an important additional effect, are involved in the so-called 'triple response' produced by intradermal injection of histamine. This response

Table 1 Classification of histamine-mediated systemic responses by severity

Severity grade Clinical symptoms Plasma histamine

I: Cutaneous Erythema, urticaria and/or dermal pruritus only si

II: Systemic Generalized skin reactions, discomfort, tachycardia, arrhythmias, medium >1

hypotension, respiratory distress

III: Life-threatening Severe hypotension, ventricular fibrillations, cardiac and respiratory arrest >12

Adapted from Ennis M and Lorenz W (1985) Hypersensitivity reactions induced by anaesthetics and plasma substitutes. In: Dean J (ed) Immunotoxicology and Immunopharmacology, pp 457-474. New York: Raven Press.

comprises a localized red spot, which is confined to a few millimeters around the site of injection and which develops within a few seconds, a flare of irregular outline that extends several centimeters beyond the original point of injection and develops more slowly, and a wheal that is discernable within 1-2 min and occupies the same area as the original red spot. The red spot results from the direct vaso-dilatory effect of histamine, while the wheal is due to an increase in capillary permeability and edema formation. The flare response is more complex and involves an axon-reflex mechanism whereby histamine stimulates afferent C-fiber nerve endings. The resulting impulses may spread antidromically into arborizations of the C fiber, leading to the release of neuropeptides, such as substance P, which act directly on the vasculature to propagate the inflammatory response.

In the human heart, histamine increases both the frequency and force of myocardial contraction as well as cardiac output. The amine also has a variety of arrhythmogenic effects, including enhancement of normal automaticity, induction of abnormal auto-maticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction and an increase in the vulnerability of the ventricles to fibrillation. A combination of Hi- and H2-directed antihistamines is needed to block this diversity of effects, indicating the involvement of both receptor types. Although somewhat controversial, both the positive inotropic and chronotropic effects of histamine appear to be largely mediated through H2 receptors, although Hj receptors may additionally be involved in the former response.

Nonvascular smooth muscle

The effect of histamine on various types of smooth muscle varies according to the source and the species; however, the amine typically contracts nonvascular smooth muscle through activation of H| receptors, although occasional relaxant responses, largely mediated through H2 receptors, are observed.

Inhalation of histamine in humans leads to bron-

choconstriction. This effect is most pronounced in asthmatic subjects in which the dose of histamine (PC20 histamine) required to produce a 20% reduction in the forced expiratory volume in 1 second (FEVi) is widely used as a measure of the degree of bronchial hyperreactivity. The initial bron-choconstrictor response to inhaled allergen in humans appears to be largely due to mast cell activation, with at least half of the effect being produced by the release of histamine and the remainder by the liberation of arachidonic acid metabolites. Among experimental animals, bronchial smooth muscle of the guinea pig is exquisitely sensitive to histamine and a profound, fatal bronchoconstriction is the characteristic feature of anaphylaxis in this species. Unusually, histamine causes relaxation in the sheep bronchus and cat trachea.

The response of gastrointestinal smooth muscle also varies with the species; however, the classical effect is again contraction and this response in the terminal ileum of the guinea pig forms the basis of the original bioassay for histamine.

Gastric acid secretion

Histamine plays an essential role in the regulation of acid secretion by oxyntic cells in the stomach. The source of this histamine varies according to the species but in humans the amine is located largely in mast cells in the gastric mucosa. The control of acid output is complex, with neurocrine, endocrine and paracrine factors acting together in interdependent fashion. In particular, acetylcholine, gastrin and histamine modulate the release process.

Two theories have evolved to account for the control of acid secretion. In the 'permission hypothesis', the oxyntic cells express acetylcholine, gastrin and histamine (H2) receptors on their surface, with the effects of acetylcholine and gastrin only being fully expressed if the histamine receptors are occupied. That is, the former agents act by 'permission' of histamine. In the 'transmission hypothesis', histamine is the final common chemostimulant for secretion, and bloodborne gastrin and neurally released acetylcho-

line act on mast cells located adjacent to the oxyntic cells to induce release of the amine. The secreted histamine then acts through H, receptors on the oxyntic cells to cause the release of acid. Histamine thus 'transmits' the actions of acetylcholine and gastrin. Of these two models, the permission hypothesis has probably received general acceptance although the transmission hypothesis has recently been vigorously revived. In any event, histamine clearly plays a key role in the process and H2 antihistamines are potent inhibitors of acid secretion induced by all physiologic mechanisms. Clinically, these agents have revolutionized the treatment of peptic ulcer disease.

The central nervous system

There are two major cellular sources of histamine in the human brain, namely mast cells and hista-minergic neurons. The mast cells occur in the largest numbers in those brain structures with a high degree of vascularization, such as median eminence, the pineal gland and the meninges. They are found in close association with blood vessels and may play a role in the control of brain blood flow and vascular permeability. Histaminergic neurons are confined exclusively to the tuberomamillary nucleus in the posterior hypothalamic region. Individual neurons project axon collaterals to many different areas and essentially innervate the whole brain. These morphologic features suggest that the central histaminergic system provides a regulatory centre for whole-brain activity. Indeed pharmacologic studies using histamine agonists, antagonists and inhibitors of the synthesis of the amine have suggested that histaminergic neurons may control the sleep-wakefulness cycle, feeding and drinking behaviours, locomotor activity, the neuroendocrine system, body temperature and circulation. Brain histamine may also be involved in aging, neurodegeneration and dementia.

Cell proliferation and cancer

It has been known for many years that histamine may promote wound healing and that proliferating tissues synthesize the amine at a very high rate. Various treatments capable of stimulating cell proliferation in the skin, such as mechanical trauma or topical application of phorbol esters and detergents, also induce local histamine synthesis. The time of maximal epidermal hyperplasia coincides with a significant increase in the tissue level of the amine and a sharp fall in the activity of the histamine-catabolizing enzyme diamine oxidase. The proliferative effect of histamine may be mediated through a novel intracellular receptor (HIC).

Newly formed, nascent histamine may also be involved in tumor growth and development. High levels of the amine and of its synthesizing enzyme histidine decarboxylase are found in growing tumors in experimental animals, and an increased activity of the enzyme has been reported in both human mammary and colorectal carcinoma tissues. In contrast, diamine oxidase activity is diminished in the latter tissue compared with the surrounding colonic mucosa. Often, the histamine concentration in the tumors does not parallel the histidine decarboxylase activity, probably indicating the rapid release or metabolism of the amine. Significantly, inhibitors ot histidine decarboxylase produce a marked inhibition of tumor growth in different animal models.

The above data would suggest a positive role for histamine in tumor induction. Consistently, studies in laboratory animals have indicated that administration of H2-receptor antagonists may lead to a decreased tumor growth and metastatic development, and an increased survival time. However, H, antihistamines promote the growth of some tumors, and abolish the antitumoral effect of the H2 blockers, while selective Hi-receptor agonists can again inhibit tumor development.

These apparently confusing findings may be rationalized into a convenient working model in which histamine plays a dual role in carcinogenesis. During tumor growth, newly synthesized histamine exerts an immunosuppressive effect by activating host suppressor T lymphocytes through H> receptors on the cell surface (see below). H2 antagonists may block this activation and facilitate the natural immune response to, and destruction of, the tumor cells. In parallel, histamine, or appropriate experi mental agonists, may exert an immunostimulatory effect by activating T contrasuppressor or effector cells through H| receptors. Blockage of this potentially beneficial effect by H, antihistamines would promote tumor development. In addition, H, and H2 receptors have recently been described on different tumor cells and histamine could then directly regulate proliferation by acting on these receptors.

Cells of the immune system

The role of histamine in allergy and atopy is well established. As discussed, the amine is released from tissue mast cells and circulating basophil leukocytes by immunoglobulin E (IgE)-dependent mechanisms. This release may be modulated by histamine H> autoreceptors which appear to be present on the sur facc of the human basophil but not the lung mast cell.

In addition, histamine may have a more general role in the regulation of both humoral and cell-mediated immune responses. The amine suppresses lymphocyte proliferation, T cell-mediated cytotoxic-

ity of allogeneic target cells, and lymphokine production. All of these effects appear to be mediated through H2 receptors. Histamine also suppresses the production of antibodies by B lymphocytes, natural killer cell cytotoxicity, complement production by monocytes, lysosomal enzyme release by neutrophils and neutrophil Chemotaxis. Thymocyte maturation, eosinophil Chemotaxis and expression of eosinophil complement receptors are also affected.

See also: Atopic allergy; Basophils; Mast cells; Hypersensitivity reactions; IgE.

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