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INTRODUCTION

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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.

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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.

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ABBREVIATIONS

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Abbreviations

ACE: angiotensin I converting enzyme

ACh: actetylcholine

ADHD: attention-deficit/hyperactivity disorder

Ang: angiotensin

AT: angiotensin receptor

AV: atrioventricular

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

5HT: serotonin

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

PG: prostaglandin

TNF-α: tumor necrosis factor alpha

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HISTAMINE

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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).

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Figure 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.

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Figure 39–2

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 only is among the most potent H2 agonists but also is an antagonist at H1 and H3 receptors and a partial ...

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