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Histamine is an endogenous biogenic amine that plays a role in the immediate allergic response and is an important regulator of gastric acid secretion. More recently, a role for histamine as a modulator of neurotransmitter release in the central and peripheral nervous systems has emerged. The cloning of four receptors for histamine and the development of subtype-specific receptor antagonists have enhanced our understanding of the physiological and pathophysiological roles of histamine. Competitive antagonists of H1 receptors are used therapeutically in treating allergies, urticaria, anaphylactic reactions, nausea, motion sickness, and insomnia. Antagonists of the H2 receptor are effective in reducing gastric acid secretion.

The peptides bradykinin and kallidin, released after activation of the kallikrein-kinin system, have cardiovascular effects similar to those of histamine and play prominent roles in inflammation and nociception. Icatibant, a competitive antagonist of the bradykinin B2 receptor, and ecallantide, a specific plasma kallikrein inhibitor, are approved for the treatment of acute episodes of edema in patients with hereditary angioedema.



ACE: angiotensin I–converting enzyme

ADHD: attention-deficit/hyperactivity disorder

Ang: angiotensin

ARNI: angiotensin receptor–neprilysin inhibitor

AT: angiotensin receptor (e.g., AT1 and AT2 receptors)

AV: atrioventricular

C1: the C1 esterase of the complement system

C1-INH: inhibitor of the activated C1 component of complement

CSF: cerebrospinal fluid

EET: epoxyeicosatrienoic acid

eNOS: endothelial nitric oxide synthase

GABA: γ-aminobutyric acid

GI: gastrointestinal

GPCR: G protein-coupled receptor

HMW: high molecular weight

5HT: serotonin (5-hydroxytryptamine)

IgE: immunoglobulin E

IL-1: interleukin-1

iNOS: inducible nitric oxide synthase

IP3: inositol trisphosphate

LMW: low molecular weight

NO: nitric oxide

PKC: protein kinase C

TNFα: tumor necrosis factor α


Histamine is a hydrophilic molecule consisting of an imidazole ring and an amino group connected by an ethylene group; histamine is biosynthesized from histidine by decarboxylation (Figure 43–1). Histamine acts through four classes of receptors, designated H1 through H4. The four histamine receptors, all G protein-coupled receptors (GPCRs), can be differentially activated by analogues of histamine (Figure 43–2) and inhibited by specific antagonists (Table 43–1).

Figure 43–1

Pathways of histamine synthesis and metabolism in humans. Histamine is synthesized from histidine by decarboxylation. Histamine is metabolized via two 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.

Figure 43–2

Structure of histamine and some H1, H2, H3, and H4 agonists. Dimaprit and 4-methylhistamine, originally identified as specific H2 agonists, have a much higher affinity for the H4 receptor; 4-methylhistamine is the most specific available H4 agonist, with about 10-fold higher affinity than dimaprit, a partial H4 agonist. Impromidine not ...

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