Histamine is a major mediator of inflammation, anaphylaxis, and gastric acid secretion; in addition, histamine plays a role in neurotransmission. Our understanding of the physiological and pathophysiological roles of histamine has been enhanced by the development of subtype-specific receptor antagonists and by the cloning of 4 receptors for histamine. Competitive antagonists of H1 receptors are used therapeutically in treating allergies, urticaria, anaphylactic reactions, nausea, motion sickness, insomnia, and some symptoms of asthma. Antagonists of the H2 receptor are effective in reducing gastric acid secretion. The peptide, bradykinin, has cardiovascular effects similar to those of histamine and plays prominent roles in inflammation and nociception.
Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by an ethylene group, biosynthesized from histidine by decarboxylation (Figure 32–1). The 4 histamine receptors, all GPCRs, can be differentially activated by analogs of histamine and inhibited by specific antagonists (Table 32–1).
Histamine synthesis and metabolism in humans. Histamine is synthesized from histidine by decarboxylation. Histamine is metabolized via 2 pathways, predominantly by methylation of the ring followed by oxidative deamination (left side of figure), and secondarily by oxidative deamination and then conjugation with ribose. These metabolites have little or no activity and are excreted in the urine. Measurement of urinary N-methylhistamine affords a reliable index of histamine production. Artifactually elevated levels of histamine in urine arise from genitourinary tract bacteria that can decarboxylate histidine. MAO, monoamine oxidase.
Table 32–1Characteristics of Histamine Receptors |Favorite Table|Download (.pdf) Table 32–1 Characteristics of Histamine Receptors
| ||H1 ||H2 ||H3 ||H4 |
|G protein coupling (2nd messengers) ||Gq/11 (↑ Ca2+; ↑ NO and ↑ cGMP) ||Gs (↑ cAMP) ||Gi/o (↓ cAMP; ↑ MAPK) ||Gi/o (↓ cAMP; ↑ Ca2+) |
|Distribution ||Smooth muscle, endothelial cells, CNS ||Gastric parietal cells, cardiac muscle, mast cells, CNS ||CNS: presynaptic ||Cells of hematopoietic origin |
|Representative agonist ||2-CH3-histamine ||Amthamine ||(R)-α-CH3-histamine ||4-CH3-histamine |
|Representative antagonist ||Chlorpheniramine ||Ranitidine ||Tiprolisant ||JNJ7777120 |
DISTRIBUTION AND BIOSYNTHESIS
DISTRIBUTION. Almost all mammalian tissues contain histamine in amounts ranging from <1 to >100 μg/g. Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid (CSF) contains significant amounts. The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial 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 (see Figure 32–1). Mast cells and basophils synthesize ...
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