Endogenous histamine 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
AT: angiotensin receptor
CNS: central nervous system
CPM/N: carboxypeptidase M/N
CSF: cerebrospinal fluid
EDHF: endothelial-derived hyperpolarizing factor
EET: epoxyeicosatrienoic acid
eNOS: endothelial nitric oxide synthase
GABA: gamma-aminobutyric acid
GPCR: G protein–coupled receptor
HMW: high molecular weight
IgE: immunoglobulin E
IL-1: interleukin 1
iNOS: inducible nitric oxide synthase
IP3: inositol triphosphate
JNK1/2: c-Jun N-terminal kinase1/2
LMW: low molecular weight
MAO: monoamine oxidase
PAF: platelet-activating factor
TNF-α: tumor necrosis factor alpha
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 39–1). Histamine acts through four classes of receptors, designated H1 through H4. The four histamine receptors, all GPCRs, can be differentially activated by analogues of histamine (Figure 39–2) and inhibited by specific antagonists (Table 39–1).
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.
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 only is among the most potent H2 agonists but also is an antagonist at H1 and H3 receptors and a partial ...