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HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS HISTAMINE

HISTORY The discovery of histamine (8-aminoethylimidazole) and the understanding of its actions parallel that of the development of the discipline of pharmacology. A complete description of the history of the discovery of histamine and its actions appears in the 11th Edition of the parent text.

Chemistry

Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by two methylene groups (Figure 24-1). The pharmacologically active form at all histamine receptors is the monocationic Ng—H tautomer, i.e., the charged form of the species depicted above, although different chemical properties of this monocation may be involved in interactions with the H1 and H2 receptors. The four classes of histamine receptors (H1-H4) can be activated differently by analogs of histamine (Table 24-1). Thus, 2-methylhistamine preferentially elicits responses mediated by H1 receptors, whereas 4(5)-methylhistamine has a preferential effect on H2 receptors. A chiral analog of histamine with restricted conformational freedom, (R)-a-methylhistamine, is the preferred agonist at H3-receptor sites, although it is a weak agonist of the H4 receptor as well. Indeed, a number of compounds have activity at both the H3 and H4 receptors.

Distribution and Biosynthesis of Histamine DISTRIBUTION

Almost all mammalian tissues contain histamine in amounts ranging from <1 to >100 mg/g. Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid (CSF) contains significant amounts. The mast cell is the predominant storage site for histamine in most tissues; in the blood, it is the basophil. The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial tree mucosa, and intestinal mucosa.

SYNTHESIS, STORAGE, AND METABOLISM

Histamine is formed by the decarboxylation of the amino acid histidine by the enzyme l-histidine decarboxylase (Figure 24-1). Every mammalian tissue that contains histamine is capable of synthesizing it from histidine by virtue of its content of l-histidine decarboxylase. Mast cells and basophils synthesize histamine and store it in secretory granules. At the secretory granule pH of ~5.5, histamine is positively charged and complexed with negatively charged acidic groups on proteases and heparin or chondroitin sulfate proteoglycans. The turnover rate of histamine in secretory granules is slow; when tissues rich in mast cells are depleted of their histamine stores, it may take weeks before concentrations return to normal levels. Non-mast cell sites of histamine formation or storage include the epidermis, the gastric mucosa, neurons within the central nervous system (CNS), and cells in regenerating or rapidly growing tissues. Turnover is rapid at these nonmast cell sites because the histamine is released continuously rather than stored. Since l-histidine decarboxylase is an inducible enzyme, the histamine-forming capacity at these sites is subject to regulation. Histamine, in the amounts normally ingested or formed by bacteria in the GI tract, is metabolized rapidly and eliminated in the urine.

Release and Functions of Endogenous Histamine

Histamine has important physiological roles. After its release from storage granules as a result of the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface, hista-mine plays a central role in immediate hypersensitivity and allergic responses. The actions of his-tamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the allergic response. In addition, certain clinically useful drugs can act directly on mast cells to release

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