Synthesis and Metabolism of Histamine

The synthesis and catabolism of histamine are depicted in Figure 14-1. Histamine is synthesized by decarboxylation of the amino acid L-histidine by histidine decarboxylase. Most histamine is stored in an inert form at its site of synthesis, and very little is freely diffusible. After synthesis and release from its storage sites, histamine acts at its targets and is rapidly metabolized through two primary pathways. Oxidative deamination leads to formation of imidazole acetic acid, while methylation, which predominates in the brain, leads to the formation of N-methylimidazole acetic acid. Both metabolites are inactive and subject to further biotransformation.

FIGURE 14–1 Synthesis and metabolism of histamine.

Storage and Release of Histamine by Mast Cells and Basophils

Histamine is stored and released primarily by mast cells. Although basophils and central neurons also use histamine, their role is not fully understood. Histamine is widely distributed, with the highest concentrations in the skin, lungs, and gastrointestinal tract mucosa, consistent with mast cell densities in these tissues.

Mast cells and basophils have high-affinity immunoglobulin E (IgE) binding sites on their surface membranes and store histamine in secretory granules. Different types of mast cells can be classified by their staining properties, anatomical locations, or susceptibility to degranulation by polyamines. Anatomically, mast cells are classified as being of mucosal or connective tissue origin. However, there are mixed populations in both tissues and additional heterogeneity within these two classes. Human mast cells differ with respect to their proteoglycan structure and content, the types of serine proteases in their storage granules, the eicosanoids synthesized and released on degranulation, and the extent to which degranulation is inhibited by cromolyn Na⁺.

In mast cell granules, histamine exists as an ionic complex with a proteoglycan, chiefly heparin sulfate, but also chondroitin sulfate E. In basophils, histamine is also stored in granules as an ionic complex, predominantly with proteoglycans. The release of histamine and other mediators from mast cells and basophils is common during allergic reactions but also can be induced by drugs and endogenous compounds to produce pseudoallergic, anaphylactoid reactions as shown in Figure 14-2. The role of mast cells in immediate and delayed hypersensitivity reactions and nonallergic disorders explains the therapeutic utility of antihistamines and degranulation inhibitors.

FIGURE 14–2 Summary of mast cell release of histamine. Some stimuli act indirectly through receptors for immunoglobulins (indentations in the membrane), whereas others act directly by causing an increase in intracellular Ca⁺⁺, which triggers the release of histamine from mast cells.

*The gastrointestinal effects of histamine at H₂ receptors are discussed in Chapter 18.

Histamine is released by noncytolytic or cytolytic degranulation. Cytolytic release occurs when the membrane is damaged, does not require energy or intracellular Ca⁺⁺, and is accompanied by leakage of cytoplasmic contents. Cytolytic release can be induced by drugs such as phenothiazines, H₁ receptor antagonists, and opioids, but the concentrations required are usually greater than therapeutic concentrations.

Noncytolytic release is evoked by binding of a specific ligand to a receptor in the plasma membrane, resulting in exocytosis of secretory granules. Noncytolytic release requires energy, depends on intracellular Ca⁺⁺, and is not accompanied by leakage of cytoplasmic contents. A classic example is degranulation of sensitized mast cells or basophils induced by cross-bridging of adjacent IgE molecules on the cell surface. This involves activation of various phospholipases, fusion of secretory granules with the plasma membrane, and extrusion of their contents. Such exocytosis results in the release of histamine, heparin, eosinophil, and neutrophil chemotactic factors; neutral proteases; and other enzymes. The release of other mediators, such as eicosanoids and platelet-activating factor, can also occur.

Noncytolytic release can also be produced by other mechanisms, often by highly basic substances. These include the polyamine compound 48/80, polypeptides such as bradykinin, substance P, formylmethionylleucinylphenylalanine, protamine, anaphylatoxins, and a protein present in bee venom. With the exception of protamine, a heparin antagonist, none of these agents has any therapeutic use, but they are likely important in pathological responses.

Noncytolytic degranulation can also be induced by several drugs including d-tubocurarine, succinylcholine, morphine, codeine (in therapeutic doses), doxorubicin, and vancomycin. The mechanism may involve activation of protein kinase A and NF-κB. Histamine release in vivo may also be produced by some plasma expanders, notably those based on cross-linked gelatin, and by radiocontrast media, especially those of high osmotic strength. Intravenous administration of these compounds is most likely to result in histamine release. Life-threatening reactions are rare but occur occasionally.

The most acute and potentially severe allergic reaction is anaphylaxis. In both animals and humans, parenterally administered histamine triggers responses that mimic the early responses of anaphylaxis, including hypotension, vasodilation, myocardial depression, dysrhythmias, urticaria, angioedema, and bronchospasm. These can be partially reversed by H₁ and H₂ receptor antagonists; however, they are most effective when administered prophylactically rather than after an acute reaction has begun. Histamine is only one of many anaphylactic mediators, but it has important effects on the production and effectiveness of others.

Noncytolytic degranulation of mast cells results in both anaphylactic and anaphylactoid reactions. Many substances can release histamine independently of IgE. However, the clinical signs and symptoms are indistinguishable from those of true anaphylaxis, because the same mediators are involved. The term anaphylactoid is used to refer to a clinical syndrome indistinguishable from anaphylaxis but caused by something other than an immune response.

Many of the solutions and drugs used in general anesthesia can produce mast cell degranulation, especially if administered intravenously. However, skeletal muscle paralysis, the effects of other drugs, and mechanical ventilation can mask signs of histamine release. Cardiac dysrhythmias or hypotension without flush, rashes, or angioedema may be seen. Indeed, most patients undergoing general anesthesia have elevated histamine levels but are relatively asymptomatic. Preoperative prophylaxis with H₁ and H₂ receptor antagonists remains controversial but is used for certain patients at risk (atopic patients and patients with previous reactions).

A summary of agents that release histamine is presented in Table 14-2. Histamine concentrations of 0.2 to 1.0 ng/mL in humans produce mild signs and symptoms, including metallic taste, headache, and nasal congestion. Concentrations exceeding 1 ng/mL produce moderate effects, including skin reactions, cramping, diarrhea, flushing, tachycardia, cardiac dysrhythmias, and hypotension. Life-threatening hypotension, ventricular fibrillation, and bronchospasm leading to cardiopulmonary arrest can occur when concentrations approach 12 ng/mL.

TABLE 14–2 Common Causal Factors Involved in Anaphylactic and Anaphylactoid Reactions

Vascular System

The effects of histamine on the systemic vasculature are complex, and different vascular beds show different responses (see Table 14-1). The predominant action is vasodilation resulting from relaxation of arteriolar smooth muscle, precapillary sphincters, and muscular venules mediated by H₁ and H₂ receptors. Vasodilation produced by H₁ receptors occurs at lower doses and is transient, whereas that caused by H₂ receptors occurs at higher doses and is sustained. Both H₁ and H₂ antagonists are required to completely block the hypotensive response.

Histamine also acts at H₁ receptors on endothelial cells in postcapillary venules to cause endothelial cells to contract and expose permeable basement membranes. This results in edema from the buildup of fluid and plasma protein in the surrounding tissue.

A summary of the actions of histamine on the vasculature is seen in the triple response of Lewis that occurs after intradermal injection. Initially a small red spot is produced at the site of injection and is then slowly surrounded by a flushed area. In a few minutes a wheal appears at the site of the original red spot. The red spot and the erythema are caused by vasodilation, with the red spot resulting from the direct actions of histamine on the cutaneous vasculature and the erythema from axon reflexes that produce vasodilation. These responses are mediated by H₁ and H₂ receptors, with H₁ receptors predominating. The wheal results from edema. Intradermal histamine also stimulates nerve endings to produce pain and itching. These local reactions represent a microcosm of the systemic effects of large doses of histamine that cause cardiovascular shock.

Heart

Histamine exerts direct and indirect actions on the human heart. Indirectly it accelerates rate and increases force of contraction because of a baroreceptor-mediated increase in sympathetic tone in response to systemic vasodilation. Direct actions on the heart are mediated primarily by H₂ receptors and include increases in rate, atrial and ventricular automaticity, and contractile force. Modest tachycardia occurs at doses of histamine that produce little change in systemic pressure, whereas low doses cause primarily indirect actions that are due to systemic vasodilation.

Respiratory System

Histamine causes bronchoconstriction in humans after inhalation or intravenous injection through activation of H₁ receptors. Normally, histamine is not especially potent; however, patients with asthma are often hyper-reactive, and therefore aerosolized histamine has been used as a provocative test for bronchial reactivity.

Histamine may also produce a modest relaxation of contracted bronchial smooth muscle through H₂ receptors, although this is not usually clinically significant. Histamine also acts on H₁ receptors to increase secretion of airway fluid and electrolytes, which may produce pulmonary edema and contribute to bronchial obstruction in patients with extrinsic asthma (see Chapter 16).

Gastrointestinal System

An important physiological function of histamine is its role as a primary mediator in the secretion of gastric acid, discussed in Chapter 18.

Other Actions

Headaches, nausea, and vomiting have also been observed in human volunteers receiving histamine. In high doses histamine stimulates catecholamine release from the adrenal medulla, an effect particularly pronounced in patients with pheochromocytoma, a catecholamine-secreting tumor of the adrenal medulla.

Central Nervous System

The role of histamine in the brain is largely inferred from results of studies in experimental animals. Postulated roles include the regulation of temperature, H₂O balance, nociception, blood pressure, and arousal. The role of individual receptor subtypes remains unclear, although considerable interest has been generated in drugs that act on H₃ receptors.